Light therapy system and methods of use

ABSTRACT

In certain embodiments a light therapy system (e.g., phototherapy device), such as for treatment of Alzheimer&#39;s disease, depression, dementia, short-term memory, or for improved learning, improved athletic performance or improved cognitive performance, is provided where the light system comprises a blue light source that operates at a frequency in the range from 20 to 50 Hz (preferably around 40 Hz), whereby the system enables retinal ganglion cells of a human to be exposed in order to stimulate brain waves (gamma oscillations in the human&#39;s brain).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 16/486,136, filed onAug. 14, 2019, which is a U.S. 371 National Phase of PCT/US2018/018250,filed on Feb. 14, 2018, which claims benefit of and priority to U.S.Ser. No. 62/595,065, filed on Dec. 5, 2017, and to U.S. Ser. No.62/459,138, filed on Feb. 15, 2017, all of which are incorporated hereinby reference in their entirety for all purposes.

STATEMENT OF GOVERNMENTAL SUPPORT

Not Applicable

BACKGROUND

Several studies have shown that light intensity and the color/hue oflight impacts human health, and various health-related technologiesbased on illumination have been proposed (see, e.g., PCT Publication: WO91/14475, U.S. Pat. No. 5,447,528, and references therein). In recentyears, blue light sources, systems comprising such sources, andwearables monitoring and recommending on blue light exposure have gaininterest (see for example US Patent Pub: 2013/011891, WO 2015/200730, WO2012/146256, US 2016/027282).

The reason is that blue light affects circadian rhythms, as the eyescontain photoreceptors with high sensitivity for blue light, and thesephotoreceptors regulate melatonin, also known as the “sleep hormone”(see e.g. Brainard et al. (2001) J. Neurosci. 21: 6405-6412).Additionally, these photoreceptors and their exposure to blue light arebelieved to regulate serotonin, also known as the “happiness” hormone(see e.g. Vandewalle et al. (2010) Proc. Natl. Acad. Sci. USA, 107:19549-19554. It is further speculated that other health andpsychological effects may be influenced via blue light, such asdepression, dementia, short-term memory and learning.

Recent results in neuroscience (Iaccarino et al. (2016) Nature 540(8):230-252) have indicated that Alzheimer's disease, a neural disorder, maybe treated by exposure to flashing lights that stimulate the brain'simmune cells to remove toxic proteins causing the disease. These resultswere obtained in laboratory studies of rodents (mice) with highlycontrolled environments, where rodents are exposed to stroboscopic lightexposure lasting at least 1 hour. The stroboscopic light typicallyoperated at a frequency of 40 Hz and helped stimulate and restoresynchronized brain activity, known as gamma oscillations, which islinked to attention and memory.

While the results are encouraging for mice there are no studies ofhumans. And there are barriers to translate the methods to humans. Oneof the problems is related to difficulties in controlling theenvironment for humans in real life. It is possible that pulsing orblinking of light can synchronize neuron activity and this might bebeneficial to old people with dementia or subjects with Alzheimer'sdisease since the neuron activity will improve and lead to better memoryand coordination of human activities. However, even thoughblinking/flashing light sources may be therapeutically effective it isbelieved they will produce significant side effects in humans (ornon-human mammalian subjects) such as visual glare, visual fatigue,ocular discomfort, headache, possible convulsions in epileptics, and thelike. Also, it is known that blinking light around 60 Hz is stressful tohumans and animals.

Therefore, it is problematic to expose humans to stroboscopic light in amanner as was done for the rodent studies. Further disadvantages of suchstroboscopic light include provocation of elliptic conditions,distraction of attention, feelings of being uncomfortable, etc.

Furthermore, it is a disadvantage for use in humans that exposure toflickering light over extended time (an hour or longer) is required.This may be impractical for a broad range of people.

SUMMARY

The wavelength sensitivity of the receptors in the retina for our visionthat form images is different from the wavelength sensitivity of thereceptors that control our hormone system and brain activities that areassociated with emotions, memory, and leaning. Using these recentdiscoveries, it was possible to develop a therapeutic lamp (phototherapydevice) that modulates the neuron responses in different parts of thebrain (such as the hippocampus) without affecting or almost withoutaffecting the vision. In certain embodiments, the lamp will typicallymodulate the brain activity with 30-60 Hz. However, when humans lookinto the lamp they will not see the stroboscopic effects. This is incontrast to ordinary lamps with 30-60 Hz flicker. The purpose of thephototherapy device is to modulate the brain response for humans withAlzheimer's disease and at the same time reduce side effects due tovisual discomfort of the blinking light.

Accordingly, in certain embodiments, a light therapy system (e.g., aphototherapy device) is disclosed herein for treatment of Alzheimer'sdisease, depression, dementia, short-term memory, or for improvedlearning, improved athletic performance or improved cognitiveperformance. In certain embodiments the light system comprises a bluelight source that operates at a frequency in the range from 20 to 50 Hz(preferably around 40 Hz), whereby the system enables retinal ganglioncells of a human to be exposed in order to stimulate brain waves (gammaoscillations in the human's brain).

In certain embodiments aspects a light therapy system is disclosedherein that operates over an extended time during a person's sleep.Typically, the extended time is one hour or more (for examplecontinuously over an hour or in multiple time segments that total morethan an hour per night). In certain embodiments the system comprises asleep mask that comprises a stroboscopic blue light source that operatesat a frequency in the range from 20 to 50 Hz (preferably around 40 Hz).The present inventors have further realized a method where a person usessuch a system, wherein the stroboscopic blue light source illuminates aperson's eyelids during sleep. The system enables retinal ganglion cellsto be exposed be a fraction of the emitted stroboscopic blue light in asufficient time and intensity to positively affect or stimulate desiredparts of the brain.

In certain embodiments a new light therapy system is provided thatcomprises a lamp or a luminaire, such as a lamp or luminaire positionedin a room, from a ceiling or a stationary lamp. In certain embodimentsthe system comprises a narrow spectrum light source with a peakintensity in the blue part of the light spectrum (preferably around 460nm) and a broad-spectrum light source covering a majority or all of thevisible light spectrum, wherein the narrow spectrum light source is astroboscopic blue light source that operates at a frequency in the rangefrom 20 to 50 Hz (preferably around 40 Hz). In certain embodiments thepower of emitted radiation from the narrow spectrum light source is lessthan the power of emitted radiation from the broad-spectrum lightsource, such as in the range from 1% to 50%, such as in the range from1% to 10%.

In certain embodiments a light therapy system is described herein thatuses two light sources comprising different wavelengths. FIG. 2 showschromaticity diagram from which it can be seen that a specific whitelight color can be generated with different wavelengths combinations. Asan example of one preferred embodiment, a system is provided, where afirst light source comprises the wavelengths 460 nm, 650 nm, and 570 nm,and a second light source comprises the wavelengths 490 nm, 770 nm (or670 nm) and 600nm. The system uses alternating combination of the lightsources, such as a 50% duty cycle at 40 HZ. I.e. the first light sourcecomprising 460 nm light is stroboscopic at 40 HZ and the second lightsource (that does not comprise light at 460 nm) is stroboscopic (e.g.,blinking) at 40 HZ. The two light sources are substantially synchronizedsuch that when the first light source is turned on, the second lightsource is turned off, and vice versa. Hence, the experience by a humanis constant white light illumination, but the white light is composed oftwo different light sources of which one provides substantially morelight from 440 nm to 480 nm at the non-visual ganglion cells at theretina and therefore increased brain activity via stroboscopic lightaround 460 nm. Alternative duty cycles are also within the scope of theinvention, such as 10% duty cycle of the first light source and 90% dutycycle of the second light source (10/90), such as 5/95, such as 25/75,such as 75/25, such as 95/5.

In certain embodiments a light therapy system and method of its use isprovided that enables positive stimulation of the brain without theaforementioned disadvantages. In particular, a light therapy system thatmay help patients with Alzheimer's disease is provided. The lighttherapy system that may also provide positive stimulation of the brainto healthy people, such as athletes, in order to optimize theirperformance.

Various embodiments contemplated herein may include, but need not belimited to, one or more of the following:

Embodiment 1: A phototherapy device, said device comprising:

-   -   a first light source that produces a light that comprises or        consists of a blue spectral component and/or green spectral        component wherein light comprising said blue and/or green        spectral component is a blinking light; and    -   a second light source that produces a light lacking a blue        and/or green spectral component or where the blue and/or green        spectral component produced by said second light source is        smaller than the blue and/or green spectral component of the        light produced by said first light source, and where said second        light source produces illumination that supplements the        illumination produced by the first light source so that the        blinking of said first light source when combined with the light        from said second light source is substantially undetectable by        human vision.

Embodiment 2: The phototherapy device of embodiment 1, wherein:

-   -   said first light source produces a light that comprises or        consists of a blue spectral component; and    -   said second light source that produces a light lacking a blue        spectral component or where the blue spectral component produced        by said second light source is smaller than the blue spectral        component of the light produced by said first light source.

Embodiment 3: The device according to any one of embodiments 1-2,wherein the blinking frequency and intensity of said first light sourceis sufficient to stimulate or to entrain brain waves in a human's brainwhen the human is exposed to said light source.

Embodiment 4: The device of embodiment 3, wherein said brain wavescomprise gamma oscillations.

Embodiment 5: The device according to any one of embodiments 1-4,wherein the frequency of blinking of said first light source ranges fromabout 20 Hz, or from about 30 Hz, or from about 35 Hz or from about 40Hz up to about 100 Hz, or up to about 80 Hz, or up to about 60 Hz, or upto about 50 Hz, or up to about 45 Hz.

Embodiment 6: The device of embodiment 5, wherein the frequency ofblinking of said first light source ranges from about 20 Hz up to about50 Hz.

Embodiment 7: The device of embodiment 5, wherein the frequency ofblinking of said first light source is about 40 Hz.

Embodiment 8: The device according to any one of embodiments 1-7,wherein the duration of the blinks of said first light source rangesfrom about 1 ms, or from about 5 ms up to about 50 ms, or up to about 40ms, or up to about 30 ms, or up to about 20 ms, or up to about 15 ms, orup to about 10 ms.

Embodiment 9: The device according to any one of embodiments 1-8,wherein the duration of the blinks of said first light source rangesfrom about 5 ms up to about 20 ms, or from about 8 ms up to about 15 ms.

Embodiment 10: The device according to any one of embodiments 1-9,wherein the color temperature of said first light source ranges fromabout 2700K, or from about 2800K, or from about 2900K up to about 6500K,or up to about 5000K, or up to about 4000K, or up to about 3500K.

Embodiment 11: The device of embodiment 10, wherein the colortemperature of said first light sources ranges from about 2900K up toabout 3100 K.

Embodiment 12: The device of embodiment 11, wherein the colortemperature of said first light source is about 3000K.

Embodiment 13: The device according to any one of embodiments 1-12,wherein said first light source provides a luminous intensity rangingfrom about 10 lm, or from about 25 lm, or from about 50 lm, or fromabout 100 lm, or from about 500 lm, up to about 10,000 lm, or up toabout 5,000 lm, or up to about 1000 lm.

Embodiment 14: The device according to any one of embodiments 1-13,wherein said first light source provides irradiance that is larger than5 mW/nm/m² in a wavelength range from about 440 nm up to about 500 nm,or from about 450 nm up to about 490 nm, or from about 450 nm up toabout 480 nm, or from about 450 nm up to about 470 nm, or from about 455nm up to about 465 nm.

Embodiment 15: The device according to any one of embodiments 1-13,wherein said first light source provides light having a totalilluminance and/or an illuminance of said blue spectral component of atleast about 10 lux, or at least about 20 lux, or at least about 30 lux,or at least about 40 lux, or at least about 50 lux, or at least about 60lux, or at least about 70 lux, or at least about 80 lux, or at leastabout 90 lux, or at least about 100 lux, or at least about 120 lux, orat least about 130 lux, or at least about 140 lux, or at least about 150lux, or at least about 160 lux, or at least about 170 lux, or at leastabout 180 lux, or at least about 190 lux, or at least about 200 lux, orat least about 300 lux, or at least about 400 lux, or at least about 500lux, or at least about 600 lux, or at least about 700 lux, or at leastabout 800 lux, or at least about 900 lux, or at least about 1000 lux.

Embodiment 16: The device according to any one of embodiments 1-13,where said second light source is a blinking light source.

Embodiment 17: The device of embodiment 16, wherein the frequency ofblinking of said second light source ranges from about 20 Hz, or fromabout 30 Hz, or from about 35 Hz or from about 40 Hz up to about 100 Hz,or up to about 80 Hz, or up to about 60 Hz, or up to about 50 Hz, or upto about 45 Hz.

Embodiment 18: The device of embodiment 16, wherein the frequency ofblinking of said second light source ranges from about 20 Hz up to about50 Hz.

Embodiment 19: The device of embodiment 16, wherein the frequency ofblinking of said second light source is about 40 Hz.

Embodiment 20: The device according to any one of embodiments 16-19,wherein the duration of the blinks of said second light source rangesfrom about 1 ms, or from about 5 ms up to about 50 ms, or up to about 40ms, or up to about 30 ms, or up to about 20 ms, or up to about 15 ms, orup to about 10 ms.

Embodiment 21: The device according to any one of embodiments 16-19,wherein the duration of the blinks of said second light source rangesfrom about 5 ms up to about 20 ms, or from about 8 ms up to about 15 ms.

Embodiment 22: The device according to any one of embodiments 1-21,wherein the color temperature of said second light source ranges fromabout 2700K, or from about 2800K, or from about 2900K up to about 6500K,or up to about 5000K, or up to about 4000K, or up to about 3500K.

Embodiment 23: The device of embodiment 22, wherein the colortemperature of said second light sources ranges from about 2900K up toabout 3100 K.

Embodiment 24: The device of embodiment 23, wherein the colortemperature of said second light source is about 3000K.

Embodiment 25: The device according to any one of embodiments 1-24,wherein said second light source provides a luminous intensity rangingfrom about 10 lm, or from about 25 lm, or from about 50 lm, or fromabout 100 lm, or from about 500 lm, up to about 10,000 lm, or up toabout 5,000 lm, or up to about 1000 lm.

Embodiment 26: The device according to any one of embodiments 1-25,wherein the difference in color temperature between said first lightsource and said second light source is less than about 30K, or less thanabout 20K, or less than about 10K, or is less than about 5K.

Embodiment 27: The device of embodiment 26, wherein the difference incolor temperature between said first light source and said second lightsource ranges from about 5K up to about 10K.

Embodiment 28: The device according to any one of embodiments 1-27,wherein the distance to the black body locus D_(UV) for said first lightsource and said second light source is less than about 0.001, or lessthan about 0.0001.

Embodiment 29: The device of embodiment 28, wherein the distance to theblackbody locus D_(V) for said first light source and said second lightsource is about 0.0001 or less.

Embodiment 30: The device according to any one of embodiments 1-29,wherein the difference in intensity between said first light source andsaid second light source is less than about 100 lux, or less than about75 lux, or less than about 50 lux, or less than about 40 lux, or lessthan about 30 lux, or less than about 20 lux, or less than about 10 lux,or less than about 5 lux, or less than about 2 lux.

Embodiment 31: The device according to any one of embodiments 1-30,wherein the first light source and the second light source emit light insubstantially the same direction.

Embodiment 32: The device of embodiment 31, wherein the difference inillumination angel between said first light source and said second lightsource is less than about 30 degrees, or less than about 25 degrees, orless than about 20 degrees, or less than about 15 degrees, or less thanabout 10 degrees, or less than about 5 degrees.

Embodiment 33: The device according to any one of embodiments 1-32,wherein said device is configured to operate said first light source outof phase with said second light source.

Embodiment 34: The device of embodiment 33, wherein the phase differencebetween said first light source and said second light source ranges fromabout 90 degrees to about 180 degrees.

Embodiment 35: The device of embodiment 34, wherein the phase differencebetween said first light source and said second light source is about180 degrees so that when said first light source is on, said secondlight source is off and vice versa.

Embodiment 36: The device according to any one of embodiments 1-35,wherein the duty cycle of said first light source and/or said secondlight source ranges from about 5% up, or from about 10%, or from about15%, or from about 20%, or from about 25%, or from about 30%, or fromabout 35%, or from about 40% up to about 90%, or up to about 85%, or upto about 80%, or up to about 75%, or up toa bout 70%, or up to about65%, or up to about 60%.

Embodiment 37: The device of embodiment 36, wherein the duty cycle ofsaid first light source and/or said second light source is about 50%.

Embodiment 38: The device according to any one of embodiments 1-37,wherein the ratio of duty cycle of said first light source to saidsecond light source ranges from about 1:10 to about 10:1, or from about1:5 to about 5:1, or from about 1:2 to about 2:1.

Embodiment 39: The device of embodiment 38, wherein the ratio of dutycycle of said first light source to said second light source is about1:1.

Embodiment 40: The device according to any one of embodiments 1-39,wherein said first light source comprises or consists of a blue spectralcomponent, a green spectral component, and an orange or red spectralcomponent.

Embodiment 41: The device of embodiment 40, wherein said first lightsource comprises or consists of a lamp that emits primarily a bluelight, a lamp that emits primarily a green light, and a lamp that emitsprimarily an orange and/or red light.

Embodiment 42: The device according to any one of embodiments 1-41,wherein the blue light comprising said first light source, or the bluespectral component of said first light source, or the blue light emittedby a lamp is in the wavelength range from about 440 nm up to about 495nm, or from about 440 nm up to about 480 nm, or from about 450 nm up toabout 480 nm, or from about 450 nm up to about 470 nm.

Embodiment 43: The device of embodiment 42, wherein the blue lightcomprising said first light source, or the blue spectral component ofsaid first light source, or the blue light emitted by a lamp has amaximum emission at about 460 nm.

Embodiment 44: The device according to any one of embodiments 1-43,wherein the green light comprising said first light source, or the greenspectral component of said first light source, or the green lightemitted by a lamp comprising said second light source is primarily inthe wavelength range from about 495 nm up to about 570 nm, or from about500 nm, or from about 510 nm, or from about 520 nm, or from about 530nm, or from about 540 nm, or from about 550 nm up to about 570 nm.

Embodiment 45: The device of embodiment 44, wherein the green lightcomprising said first light source, or the green spectral component ofsaid first light source, or the green light emitted by a lamp isprimarily in the wavelength range from about 550 nm up to about 570 nm.

Embodiment 46: The device of embodiment 45, wherein the green lightcomprising said first light source, or the green spectral component ofsaid first light source, or the green light emitted by a lamp has amaximum emission at about 550 nm or at about 570 nm.

Embodiment 47: The device according to any one of embodiments 1-46,wherein the orange/red light comprising said first light source, or theorange/red spectral component of said first light source, or theorange/red light emitted by a lamp comprising said second light sourceis primarily in the wavelength range from about 590 nm up to about 750nm, or from about 600 nm up to about 700 nm, or up to about 650 nm.

Embodiment 48: The device of embodiment 47, wherein the orange/red lightcomprising said first light source, or the orange/red spectral componentof said first light source, or the orange/red light emitted by a lamp isprimarily in the wavelength range from about 600 nm up to about 650 nm.

Embodiment 49: The device of embodiment 48, wherein the orange/red lightcomprising said first light source, or the orange/red spectral componentof said first light source, or the orange/red light emitted by a lamphas a maximum emission at about 600 nm or at about 650 nm.

Embodiment 50: The device according to any one of embodiments 1-49,wherein:

-   -   said second light source comprises or consists of a blue/green        spectral component, an orange spectral component, and a red/far        red spectral component; or    -   said second light source comprises or consists of a green        spectral component, and an orange/red spectral component.

Embodiment 51: The device of embodiment 50, wherein:

-   -   said second light source comprises or consists of a lamp that        emits primarily a blue/green light, a lamp that emits primarily        an orange light, and a lamp that emits primarily a red/far red        light; or    -   said second light source comprises or consists of a lamp that        emits primarily a green light, and a lamp that emits primarily        an orange/red light.

Embodiment 52: The device of embodiment 51, wherein said second lightsource comprises or consists of a lamp that emits primarily a blue/greenlight, a lamp that emits primarily an orange light, and a lamp thatemits primarily a red/far red light.

Embodiment 53: The device of embodiment 52, wherein the blue/green lightcomprising said second light source, or the blue/green spectralcomponent of said second light source, or the blue/green light emittedby a lamp comprising said second light source is primarily in thewavelength range from about 490 nm up to about 570 nm, or from about 500nm, or from about 510 nm, or from about 520 nm, or from about 530 nm, orfrom about 540 nm, or from about 550 nm up to about 570 nm.

Embodiment 54: The device of embodiment 53, wherein the blue lightcomprising said second light source, or the blue spectral component ofsaid second light source, or the blue light emitted by a lamp has amaximum emission at about 490 nm.

Embodiment 55: The device according to any one of embodiments 52-54,wherein the orange light comprising said second light source, or theorange spectral component of said second light source, or the orangelight emitted by a lamp comprising said second light source is primarilyin the wavelength range from about 590 nm up to about 620 nm, or fromabout 590 nm up to about 610 nm.

Embodiment 56: The device of embodiment 55, wherein the orange lightcomprising said second light source, or the orange spectral component ofsaid second light source, or the orange light emitted by a lampcomprising said second light source has a maximum emission about 600 nm.

Embodiment 57: The device according to any one of embodiments 52-56,wherein the red/far red light comprising said second light source, orthe red/far red spectral component of said second light source, or thered/far red light emitted by a lamp comprising said second light sourceis primarily in the wavelength range from about 620 nm, up to about 770nm, or from about 650 nm up to about 750 nm, or from about 670 nm up toabout 700 nm.

Embodiment 58: The device of embodiment 57, wherein the red/far redlight comprising said second light source, or the red/far red spectralcomponent of said second light source, or the red/far red light emittedby a lamp comprising said second light source is primarily is 670 nm orabout 770 nm.

Embodiment 59: The device of embodiment 51, wherein said second lightsource comprises or consists of a lamp that emits primarily a greenlight, and a lamp that emits primarily an orange/red light.

Embodiment 60: The device of embodiment 59, wherein the green lightcomprising said second light source, or the green spectral component ofsaid second light source, or the green light emitted by a lampcomprising said second light source is primarily in the wavelength rangefrom about 495 nm up to about 570 nm, or from about 500 nm, or fromabout 510 nm, or from about 520 nm, or from about 530 nm, or from about540 nm, or from about 550 nm up to about 570 nm.

Embodiment 61: The device of embodiment 60, wherein the green lightcomprising said second light source, or the green spectral component ofsaid second light source, or the green light emitted by a lamp isprimarily in the wavelength range from about 500 nm up to about 550 nm.

Embodiment 62: The device of embodiment 61, wherein the green lightcomprising said second light source, or the green spectral component ofsaid second light source, or the green light emitted by a lamp has amaximum emission at about 500 nm.

Embodiment 63: The device according to any one of embodiments 59-62,wherein the orange/red light comprising said second light source, or theorange/red spectral component of said second light source, or theorange/red light emitted by a lamp comprising said second light sourceis primarily in the wavelength range from about 590 nm up to about 750nm, or from about 600 nm up to about 700 nm, or up to about 650 nm.

Embodiment 64: The device of embodiment 63, wherein the orange/red lightcomprising said second light source, or the orange/red spectralcomponent of said second light source, or the orange/red light emittedby a lamp is primarily in the wavelength range from about 600 nm up toabout 650 nm.

Embodiment 65: The device of embodiment 64, wherein the orange/red lightcomprising said second light source, or the orange/red spectralcomponent of said second light source, or the orange/red light emittedby a lamp has a maximum emission at about 600 nm or at about 610 nm.

Embodiment 66: The device according to any one of embodiments 1-65,wherein said phototherapy device produces a light that is perceived as acolor other than white.

Embodiment 67: The device of embodiment 66, wherein said first lightsource comprises or consists of a green spectral component and a redspectral component and said second light source comprises a yellowspectral component.

Embodiment 68: The device according to any one of embodiments 66-67,wherein first light source comprises a green spectral component with amaximum emission at about 530 nm.

Embodiment 69: The device according to any one of embodiments 66-68,wherein said first light source comprises a red spectral component witha maximum emission at about a 630 nm.

Embodiment 70: The device according to any one of embodiments 66-69,wherein said second light source comprise or consists of a yellowspectral component.

Embodiment 71: The device of embodiment 70, wherein said second lightsource comprises a yellow spectral component with a maximum emission atabout 580 nm.

Embodiment 72: The device of embodiment 66, wherein said first lightsource comprises or consists of a blue spectral component and a yellowspectral component.

Embodiment 73: The device of embodiment 72, wherein said first lightsource comprises a blue spectral component with a maximum emission atabout 480nm.

Embodiment 74: The device according to any one of embodiments 72-73,wherein said first light source comprises a yellow spectral componentwith a maximum emission at about 575 nm.

Embodiment 75: The device according to any one of embodiments 72-74,wherein said second light source comprise or consists of a greenspectral component and a red spectral component.

Embodiment 76: The device according to any one of embodiments 72-75,wherein said second light source comprises a green spectral componentwith a maximum emission at about 510 nm.

Embodiment 77: The device according to any one of embodiments 72-76,wherein said second light source comprises a red spectral component witha maximum emission at about 600 nm.

Embodiment 78: The device according to any one of embodiments 1-77,wherein said first light source comprises one or more light emittingdiodes (LEDs).

Embodiment 79: The device of embodiment 78, wherein the first lightsource comprises at least one different LED for each spectral component.

Embodiment 80: The device according to any one of embodiments 1-79,wherein said second light source comprises one or more light emittingdiodes.

Embodiment 81: The device of embodiment 80, wherein the second lightsource comprises at least one different LED for each spectral component.

Embodiment 82: The device according to any one of embodiments 1-81,wherein said first light source and said second light source aredisposed in a diffuser.

Embodiment 83: The device according to any one of embodiments 1-82,wherein said device comprises a luminaire.

Embodiment 84: The device according to any one of embodiments 1-82,wherein said device comprises a table lamp or an overhead lamp.

Embodiment 85: The device according to any one of embodiments 1-82,wherein said device is configured for mounting proximate, at, and/orattached to a frame of a window.

Embodiment 86: The device according to any one of embodiments 1-82,wherein said device comprises a face or eye mask.

Embodiment 87: The device according to any one of embodiments 1-85,wherein said first light source and said second light source are in asingle unit or housing.

Embodiment 88: The device according to any one of embodiments 1-85,wherein said first light source and said second light source are indifferent units or housings.

Embodiment 89: The device according to any one of embodiments 1-88,wherein said device comprises a controller that controls one or more ofthe intensity of said first light source and/or said second lightsource, the blinking rate of said first light source and/or said secondlight source, the phase of said first light source and/or said secondlight source, the spectral composition of said first light source and/orsaid second light source, and the intensity of said first light sourceand/or said second light source.

Embodiment 90: The device of embodiment 89, wherein said controller isconfigured to controls said first light source and/or said second lightsource as a function of the time of day.

Embodiment 91: The device according to any one of embodiments 89-90,said controller is configured to in response to movement in a room.

Embodiment 92: The device according to any one of embodiments 89-90,said controller is configured to interface with a computer, cell phone,or tablet.

Embodiment 93: A system comprising:

-   -   a device according to any one of embodiments 1-92; and    -   one or more of a personal health sensor configured to be worn by        a human, a personal environment sensor, a cell phone configured        with an application to interface with said device, a computer        configured with an application not interface with said device,        and a tablet configured to interface with said device.

Embodiment 94: The system of embodiment 93, wherein said systemcomprises one or more devices selected from the group consisting of asmart phone, a smart watch, an activity tracker, an ambient lightsensor, a GPS, an accelerometer, and a clock.

Embodiment 95: A method of treating a subject having a neurodegenerativecondition selected from the group consisting of dementia, mild cognitiveimpairment, and Alzheimer's disease, said method comprising:

-   -   exposing said subject to blinking blue light at a frequency        ranging from about 20 Hz up to about 60 Hz, or from about 30 Hz        up to about 50 Hz, or from about 35 Hz up to about 45 Hz, or at        about 40 Hz, at an intensity and duration sufficient to mitigate        a symptom, or slow or stop the progression of said        neurodegenerative condition.

Embodiment 96: The method of embodiment 95, wherein said blue lightcomprises a blue light or a blue spectral component of a light in thewavelength range from about 440 nm up to about 495 nm, or from about 440nm up to about 480 nm, or from about 450 nm up to about 480 nm, or fromabout 450 nm up to about 470 nm.

Embodiment 97: The method of embodiment 96, wherein the blue light orblue spectral component of a light has a maximum at about 460 nm.

Embodiment 98: The method according to any one of embodiments 96-97,wherein said blinking blue light is administered by a device accordingto any one of embodiments 1-92, or a system according to any one ofembodiments 93-94.

Embodiment 99: The method according to any one of embodiments 95-98,wherein said method comprises ameliorating one or more symptoms ofAlzheimer's disease, and/or reversing Alzheimer's disease, and/orreducing the rate of progression of Alzheimer's disease.

Embodiment 100: The method according to any one of embodiments 95-98,wherein said method comprises preventing or delaying the onset of apre-Alzheimer's condition and/or cognitive dysfunction, and/orameliorating one or more symptoms of a pre-Alzheimer's condition and/orcognitive dysfunction, or preventing or delaying the progression of apre-Alzheimer's condition or cognitive dysfunction to Alzheimer'sdisease.

Embodiment 101: The method of embodiment 100, wherein said method is amethod of preventing or delaying the transition from a cognitivelyasymptomatic pre-Alzheimer's condition to a pre-Alzheimer's cognitivedysfunction.

Embodiment 102: The method of embodiment 100, wherein said method is amethod of preventing or delaying the onset of a pre-Alzheimer'scognitive dysfunction, or ameliorating one or more symptoms of apre-Alzheimer's cognitive dysfunction.

Embodiment 103: The method of embodiment 100, wherein said methodcomprises preventing or delaying the progression of a pre-Alzheimer'scognitive dysfunction (e.g., MCI) to Alzheimer's disease.

Embodiment 104: The method according to any one of embodiments 99-103,wherein said subject is a human.

Embodiment 105: The method according to any one of embodiments 99-104,wherein said subject exhibits biomarker positivity of AP in a clinicallynormal human subject age 50 or older.

Embodiment 106: The method according to any one of embodiments 99-104,wherein said subject exhibits asymptomatic cerebral amyloidosis.

Embodiment 107: The method according to any one of embodiments 99-106,wherein said subject exhibits cerebral amyloidosis in combination withdownstream neurodegeneration.

Embodiment 108: The method according to any one of embodiments 99-107,wherein said subject exhibits cerebral amyloidosis in combination withdownstream neurodegeneration and subtle cognitive/behavioral decline.

Embodiment 109: The method according to any one of embodiments 107-108,wherein said downstream neurodegeneration is determined by one or moreelevated markers of neuronal injury selected from the group consistingof tau, and FDG uptake.

Embodiment 110: The method according to any one of embodiments 106-109,wherein said cerebral amyloidosis is determined by PET, or CSF analysis,and structural MRI (sMRI).

Embodiment 111: The method according to any one of embodiments 100-110,wherein said subject is a subject diagnosed with mild cognitiveimpairment.

Embodiment 112: The method according to any one of embodiments 100-111,wherein said subject shows a clinical dementia rating above zero andbelow about 1.5.

Embodiment 113: The method according to any one of embodiments 99-112,wherein the subject is at risk of developing Alzheimer's disease.

Embodiment 114: The method according to any one of embodiments 99-113,wherein the subject has a familial risk for having Alzheimer's disease.

Embodiment 115: The method according to any one of embodiments 99-113,wherein the subject has a familial Alzheimer's disease (FAD) mutation.

Embodiment 116: The method according to any one of embodiments 99-113,wherein the subject has the APOE ε4 allele.

Embodiment 117: The method according to any one of embodiments 100-116,wherein administration of said compound delays or prevents theprogression of MCI to Alzheimer's disease.

Embodiment 118: The method according to any one of embodiments 95-117,wherein said method produces a reduction in the CSF of levels of one ormore components selected from the group consisting of Aβ42, sAPPβ,total-Tau (tTau), phospho-Tau (pTau), APPneo, soluble Aβ40, pTau/Aβ42ratio and tTau/Aβ42 ratio, and/or an increase in the CSF of levels ofone or more components selected from the group consisting of Aβ42/Aβ40ratio, Aβ42/Aβ38 ratio, sAPPα, sAPPα/sAPPβ ratio, sAPPα/Aβ40 ratio, andsAPPα/Aβ42 ratio.

Embodiment 119: The method according to any one of embodiments 95-118,wherein said method produces a reduction of the plaque load in the brainof the subject.

Embodiment 120: The method according to any one of embodiments 95-119,wherein said method produces a reduction in the rate of plaque formationin the brain of the subject.

Embodiment 121: The method according to any one of embodiments 95-120,wherein said method produces an improvement in the cognitive abilitiesof the subject.

Embodiment 122: The method according to any one of embodiments 95-121,wherein said method produces an improvement in, a stabilization of, or areduction in the rate of decline of the clinical dementia rating (CDR)of the subject.

Embodiment 123: The method according to any one of embodiments 95-122,wherein the subject is a human and said method produces a perceivedimprovement in quality of life by the human.

Embodiment 124: The method according to any one of embodiments 95-123,wherein said method further comprises administering to said subject adrug for the treatment of a cognitive disorder and/or Alzheimer'sdisease.

Embodiment 125: The method of embodiment 124, wherein said drugcomprises a cholinesterase inhibitor.

Embodiment 126: The method of embodiment 124, wherein said drugcomprises a drug selected from the group consisting of donepezil,galantamine, memantine, rivastigmine, and Memantine+donepezil.

Embodiment 127: A method of treating depression, short-term memory loss,of improving memory, of improving cognition, of improving sleep, and/orof improving athletic performance in a subject, said method comprising:

-   -   exposing said subject to blinking blue light at a frequency        ranging from about 20 Hz up to about 60 Hz, or from about 30 Hz        up to about 50 Hz, or from about 35 Hz up to about 45 Hz, or at        about 40 Hz, at an intensity and duration sufficient to mitigate        a symptom, or slow or stop the progression of said        neurodegenerative condition.

Embodiment 128: The method of embodiment 127, wherein said blue lightcomprises a blue light or a blue spectral component of a light in thewavelength range from about 440 nm up to about 495 nm, or from about 440nm up to about 480 nm, or from about 450 nm up to about 480 nm, or fromabout 450 nm up to about 470 nm.

Embodiment 129: The method of embodiment 128, wherein the blue light orblue spectral component of a light has a maximum at about 460 nm.

Embodiment 130: The method according to any one of embodiments 128-129,wherein said blinking blue light is administered by a device accordingto any one of embodiments 1-92, or a system according to any one ofembodiments 93-94.

Embodiment 131: A light therapy system, such as for treatment ofAlzheimer's disease, depression, dementia, short-term memory, or forimproved learning, improved athletic performance or improved cognitiveperformance, the light system comprising a blue light source thatoperates at a frequency in the range from 20 to 50 Hz (preferably around40 Hz), whereby the system enables retinal ganglion cells of a human tobe exposed in order to stimulate brain waves (gamma oscillations in thehuman's brain).

Embodiment 132: A light therapy system, such as for treatment ofAlzheimer's disease, depression, dementia, short-term memory, or forimproved learning, improved athletic performance or improved cognitiveperformance, the light system comprising a sleep mask that comprises ablue light source for illumination of a human's eye lids, said bluelight operates at a frequency in the range from 20 to 50 Hz (preferablyaround 40 Hz), whereby the system enables retinal ganglion cells of ahuman wearing the mask to be exposed be a fraction of the emitted bluelight (a fraction that penetrates though the eye lids) over a total timeperiod of more than 1 hour in order to stimulate brain waves (gammaoscillations in the human's brain).

Embodiment 133: A light therapy system, such as for treatment ofAlzheimer's disease, depression, dementia, short-term memory, or forimproved learning, improved athletic performance or improved cognitiveperformance, the light system comprising comprises a narrow spectrumlight source with a peak intensity in the blue part of the lightspectrum, such as around 460 nm, and a broad spectrum light sourcecovering a majority or all of the visible light spectrum, wherein thenarrow spectrum light source is a stroboscopic blue light source thatoperates at a frequency in the range from 20 to 60 Hz (preferably around40 Hz) and has a majority of its power within the wavelength range from440 nm to 480 nm, the broad spectrum light source is a continuous lightsource that has a majority of its power outside the wavelength rangefrom 440 nm to 480 nm, whereby the two light sources in combinationprovides a substantially white light illumination.

Embodiment 134: A light therapy system, such as for treatment ofAlzheimer's disease, depression, dementia, short-term memory, or forimproved learning, improved athletic performance or improved cognitiveperformance, the light system comprising comprises a first light sourceand a second light source, wherein the light sources operate at afrequency in the range from 20 to 60 Hz (preferably around 40 Hz) andare synchronized in a manner such that the combined light from the lightsources are substantially constant in power.

Embodiment 135: A light therapy system according to embodiment 134,wherein said first light source has a spectral component around 460 nmthat is larger than a spectral component of around 460 nm of said secondlight source.

Embodiment 136: A light therapy system according to any one ofembodiments 131 to 135, wherein said light source(s) comprise LED-basedlight source(s).

Embodiment 137: A light therapy system according to any one ofembodiments 131-136, wherein said first light source comprises thewavelengths 460 nm, 650 nm, and 570 nm, and a second light sourcecomprises the wavelengths 490 nm, 770 nm and 600nm.

Embodiment 138: A method of treating of Alzheimer's disease, depression,dementia, and/or improving short-term memory, and/or improving learning,and/or improving athletic performance, and/or improving cognitiveperformance in a mammal, said method comprising:

-   -   exposing said mammal to a light source comprising an oscillating        blue light that operates at a frequency ranging from about 20 Hz        to about 50 Hz.

Embodiment 139: A method of using a light therapy system according toany of the embodiments 131-137, wherein the system is used by anindividual (for example a patient, a prisoner, a student, an elderlyindividual in a private home, or an athlete) for optimizingrehabilitation, recovery, physiotherapy, practice, training and/orperformance at competition.

Definitions

The terms “subject,” “individual,” and “patient” may be usedinterchangeably herein and typically refer to a mammal, in certainembodiments a human or a non-human primate. While the phototherapydevices and systems described herein are described with respect to usein humans, they are also suitable for animal, e.g., veterinary use.Thus, certain illustrative organisms include, but are not limited tohumans, non-human primates, canines, equines, felines, porcines,ungulates, lagomorphs, and the like. Accordingly, certain embodimentscontemplate use of the phototherapy devices and systems described hereinwith domesticated mammals (e.g., canine, feline, equine), laboratorymammals (e.g., mouse, rat, rabbit, hamster, guinea pig), andagricultural mammals (e.g., equine, bovine, porcine, ovine), and thelike. The term “subject” does not require one to have any particularstatus with respect to a hospital, clinic, or research facility (e.g.,as an admitted patient, a study participant, or the like). Accordingly,in various embodiments, the subject can be a human (e.g., adult male,adult female, adolescent male, adolescent female, male child, femalechild) under the care of a physician or other health worker in ahospital, psychiatric care facility, as an outpatient, or other,clinical context. In certain embodiments, the subject may not be underthe care or prescription of a physician, or other, health worker. Incertain embodiments the subject may not be under the care a physician orhealth worker and, in certain embodiments, may self-prescribe and/orself-administer a phototherapy regimen using, e.g., the devices and/orsystems described herein.

The terms “treatment,” “treating,” or “treat” as used herein, refer toactions that produce a desirable effect on the symptoms or pathology ofa disease or condition, particularly those that can be effectedutilizing the phototherapy devices and phototherapy regimen describedherein, and may include, but are not limited to, even minimal changes orimprovements in one or more measurable markers of the disease orcondition being treated. Treatments also refers to delaying the onsetof, retarding or reversing the progress of, reducing the severity of, oralleviating or preventing either the disease or condition to which theterm applies, or one or more symptoms of such disease or condition.“Treatment,” “treating,” or “treat” does not necessarily indicatecomplete eradication or cure of the disease or condition, or associatedsymptoms thereof. In one embodiment, treatment comprises improvement ofat least one symptom of a disease being treated. The improvement may bepartial or complete. The subject receiving this treatment is any subjectin need thereof. Exemplary markers of clinical improvement will beapparent to persons skilled in the art.

The terms “Planckian locus” or “black body locus” or “D_(UV)” are usedinterchangeably and refer to the path or locus that the color of anincandescent black body would take in a particular chromaticity space asthe blackbody temperature changes. It goes from deep red at lowtemperatures through orange, yellowish white, white, and finally bluishwhite at very high temperatures.

A color space is a three-dimensional space; that is, a color isspecified by a set of three numbers (the CIE coordinates X, Y, and Z,for example, or other values such as hue, colorfulness, and luminance)which specify the color and brightness of a particular homogeneousvisual stimulus. A chromaticity is a color projected into atwo-dimensional space that ignores brightness. For example, the standardCIE XYZ color space projects directly to the corresponding chromaticityspace specified by the two chromaticity coordinates known as x and y,making the familiar chromaticity diagram shown in the figure. ThePlanckian locus, the path that the color of a black body takes as theblackbody temperature changes, is often shown in this standardchromaticity space.

The “color temperature” of a light source is the temperature of an idealblack-body radiator that radiates light of a color comparable to that ofthe light source. Color temperature is conventionally expressed inkelvin, using the symbol K, a unit of measure for absolute temperature.

A “spectral component” of a light source indicates that the lightproduced by the light source comprises light within a particularreferenced wavelength range. Approximate wavelength and frequency rangesfor various colors are shown in Table 1, and when colors or spectralcomponents are referenced with respect to colors the light consists orcomprises illumination within the recited ranges.

TABLE 1 Approximate wavelength and frequency ranges for various colors.Color Wavelength Frequency violet 380-450 nm 668-789 THz blue 450-495 nm606-668 THz green 495-570 nm 526-606 THz yellow 570-590 nm 508-526 THzorange 590-620 nm 484-508 THz red 620-750 nm 400-484 THz

Thus, for example, a light source having or comprising a blue spectralcomponent emits illumination at least a portion of which falls withinthe 450 nm to 495 nm wavelength range. A light source consisting of ablue spectral component emit illumination all of which falls within the450 nm to 495 nm wavelength range.

The terms “flickering” or “blinking”, or “stroboscopic” when used hereinwith respect to a light source or a component of a light sourceindicates that the light source or the component of the light sourcealternates between two different brightness states (e.g., a high stateand a low state) in at least one spectral component. In certainembodiments the light source, or alternates between a high state and alow state in all spectral components emitted by the light, although thebrightness/intensity of the high and low state may differ in differentspectral components. In certain embodiments the light source alternatesbetween two different brightness states in all visible spectralcomponents of the light source. In certain embodiments the light sourcealternates between an on state and an off state. In certain embodimentsthe light source, or a spectral component thereof, alternates between a“high” illumination state (e.g., full on/brightness) and a lowerillumination state. In certain embodiments the lower state has abrightness that is about 75% or less, or about 70% or less, or about 60%or less, or about 50% or less, or about 40% or less, or about 30% orless, or about 20% or less, or about 10% or less, or about 5% or less,or about 3% or less, or about 1% or less, than the high state in atleast one spectral component.

The “duration of a blink” refers to the time duration between the lowestillumination state and the next following lowest illumination state.

That a spectral component produced by a second light source is less thana spectral component produced by a first light source indicates that theluminance produced by the referenced spectral component in the secondlight source is less than the luminance produced by the spectralcomponent in the first light source. In certain embodiments this ismeasured as the luminance at the wavelength of maximum intensityproduced by the lamp(s) providing that spectral component. In certainembodiments this is measured as the luminance integrated across the fullwavelength range of the spectral component at issue. In certainembodiments the second light source luminance in the spectralcomponent(s) at issue is less than about 60%, or less than about 50%, orless than about 40%, or less than about 30%, or less than about 20%, orless than about 10%, or less than about 5%, or less than about 3%, orless than about 2%, or less than about 1%. In certain embodiments thesecond light source provides no illumination in the spectral componentof interest.

The “critical flicker fusion frequency”, “flicker fusion threshold”, or“flicker fusion rate” refers to a concept in the psychophysics ofvision. It is defined as the frequency at which an intermittent (e.g.,blinking) light stimulus appears to be completely steady to the averagehuman observer. Flicker fusion threshold is related to persistence ofvision

The phrase “source is substantially undetectable by human vision” whenused with respect to a flickering or blinking light means that a humanilluminated by or observing the illumination cannot see the blinkingcomponent of the light and instead perceives the illumination assubstantially constant, even where the frequency of the blinkinglight/light component is below the flicker fusion threshold. Thecritical fusion frequency depends on the luminance of the stimulus andits size (see, e.g., Hecht and Smith (1936) J. Gen. Physiol. 19(6):979-89). For a large, high luminance stimulus covering the fovea, like afull screen white field on a CRT, flicker fusion occurs at about 60 Hz.

The terms “light source” and “illumination source” are usedinterchangeably and refer to a device that provides light typicallywithin the visible spectrum for humans. The light source can compriseone or a plurality of lamps and can deliver light comprising, orconsisting of, specific spectral components.

The terms “lamp” or “bulb” are used interchangeably and refer to devicethat creates light, typically by the application of electricity. A lampincludes, but is not limited to light emitting diode (LED), a laser, atungsten bulb (that may be filtered to provide specific spectralcomponent(s)), a halogen bulb (that may be filtered to provide specificspectral component(s)), a xenon bulb (that may be filtered to providespecific spectral component(s)), and the like.

When referring to the difference in illumination angel between the firstlight source and the second light source determined with respect to thecenter ray produced by the light source. In certain embodiments thedifference in illumination angle refers to the illumination angle of thelight as it passes from the phototherapy device rather than from thefirst or second light source. Accordingly, where the phototherapy devicecomprises a diffuser or collimator, the difference in illumination anglebetween the first light source and second light source is identical.

A “duty cycle” is the fraction of one period in which a signal or systemis active. Duty cycle is commonly expressed as a percentage or a ratio.Thus, a 60% duty cycle means the signal (e.g., light source) is on 60%of the time but off 40% of the time.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 schematically shows one illustrative, but non-limiting embodimentof a phototherapy device described herein. As illustrated the device 100comprises a first light source 101 comprising lamps 103, 104, and 105, asecond light source 102 comprising lamps 106 and 107, a diffuser 108, acontroller 110 comprising controls for one or more of on/off and/orbrightness 112, blink frequency 113, phase and/or duty cycle 114, colortemperature and/or hue 115, and the like.

FIG. 2 schematically illustrates the use of a blue light therapy systemwith a blue stroboscopic light that stimulates neural activity todecrease amyloid plague formation in the brain.

FIG. 3 shows a chromaticity diagram illustrating how a specific whitelight color can generated with different wavelengths combinations

FIG. 4A schematically illustrates one embodiment of the modulation oftwo light sources for a light therapy device described herein wherelight is modulated between a full-on and an off state. FIG. 4Bschematically illustrates one embodiment of the modulation of two lightsources for a light therapy device described herein where light ismodulated between a high state (e.g., full-on) and a low, but non-zero(not off) state.

FIG. 5 shows another schematic illustration of the modulation of twoalternating light sources in a sinusoidal pattern.

FIG. 6, panel A, shows an illustrative, but non-limiting chromaticitydiagram for the first light source (e.g. LED1). In this illustration,the light source consists the colors with wavelengths 460 nm, 550 nm,and 600 nm. FIG. 6, panel B shows an illustrative, but non-limitingchromaticity diagram for the second light source (e.g., LED2).

FIG. 7 illustrates one embodiments of the power supply voltage for thetwo light sources (first light source and second light source). In thisillustrative, but non-limiting embodiment, the voltages are 180 degreesout of phase. The combination of light produced by the first lightsource and the second light source results in a continuous substantiallyconstant illumination.

FIG. 8 shows one illustrative, but non-limiting embodiment of a circuitthat can drive a light source comprising a phototherapy device describedherein.

FIG. 9 shows a prototype of one embodiment of a phototherapy devicedescribed herein.

FIG. 10 shows an illustrative diffuser mounted on top of LEDs comprisinga light source.

FIG. 11 shows an illustrative, but non-limiting chromaticity diagram forthe generation of a colored (e.g., yellow) light in a phototherapydevice.

FIG. 12 illustrates an Arduino micro-controller useful in thephototherapy devices described herein.

FIG. 13 illustrates LEDs with mounts, driver electronics andmicro-controller all wired up.

FIG. 14 shows a close-up of LEDs in one embodiment of the devicesdescribed herein.

DETAILED DESCRIPTION

New studies have shown that flickering light at 40 hertz can reduce thebeta amyloid plaque production (early clinical signs of Alzheimer's) inan Alzheimer's Disease (AD) mouse model by stimulating the brain waveactivity (e.g., gamma oscillations) in the visual cortex (see, e.g.,Iaccarino et al. (2016) Nature, 540(7632): 2300. However, trials on micecannot be duplicated in humans due to the negative side effects offlickering light, essentially hampering the opportunity to pursue thismethodology in clinical trials.

In particular, flickering light applied to humans has been observed toinduce convulsions (e.g., in epileptics or subject prone to epilepsy),to induce headaches, to cause visual fatigue, to inhibit focus and/orattention, to create feelings of ocular discomfort and/or emotionaldiscomfort, to provide undesirable glare. It is also known that blinkinglight at certain frequencies induces stress in humans and non-humanmammals. These adverse effects, while perhaps tolerable in certainsubjects for very short time intervals, are believed to prohibit thetherapeutic application of flickering light regimes to humans overprolonged time intervals (e.g., greater than about 10 minutes, orgreater than about 15 minutes, or greater than about 30 minutes, orgreater than about 45 minutes, or greater than about 1 hour, or greaterthan about 1.5 hours, or greater than about 2 hours, or greater thanabout 2.5 hours, or greater than about 3 hours).

In various embodiments phototherapy devices are provided that deliver ablinking illumination effective to induce or entrain brain oscillations(e.g., gamma oscillations) and thereby mitigate or prevent variousneurodegenerative conditions including but not limited to Alzheimer'sdisease, mild cognitive impairment (MCI), dementia, and the like. Thephototherapy devices are designed so that the blinking light isgenerally imperceptible by the subject (e.g., a human) which remainingeffective to induce and/or to entrain the brain oscillations. As theblinking cannot be observed by the subject, it is believed the adverseeffects of blinking light referenced above can substantially be avoidedproviding for effective and prolonged phototherapy treatments.

Without being bound by a particular theory it is believed that thephototherapy systems and devices described herein find utility in theprevention and/or treatment of various neurodegenerative conditionsincluding, but not limited to Alzheimer's disease (AD), dementia, mildcognitive impairment (MCI) and the like. This has important implicationsfor public health.

One of the biggest demographic challenges in Europe and the US is therapidly growing number of people with Alzheimer's and dementia (˜30% ofthe world population has or will develop the neurodegenerative disease).Dementia is one of the leading causes of death among those 60 years andover. The increase in the number of Europeans and Americans living withdementia is already creating immense challenges for the health andsocioeconomic systems and will cost the US nation more than 250 billiondollars in healthcare. For most people, the cognitive decline startswith a failing memory and a lack of perception and attention.

It is important to notice that Alzheimer's and dementia are practicallyuntreatable today. Despite decades of scientific and pharmaceuticalresearch, patients are left without any hope of recovery and reversal ofthe disease and at best current available treatment can alleviate thesymptoms and only slightly slow down disease progression.

It is believed the phototherapy devices and systems described herein canbe used to or the treatment and/or prophylaxis of the neurodegenerativebrain disease chronic traumatic encephalopathy (CTE) which has beenassociated with Alzheimer's-like symptoms and is experienced by athleteswho has suffered repeated head traumas (series of concussions). Recentyears have uncovered severe problems in the sports area for Americanfootball players, with widespread problems in their post-career withmemory loss, confusion, aggression, rage and, at times, suicidalbehaviour.

Related to the above, sleep-deprived living, such as stressful lives,night-shift working, and hormone-disturbing substances, are adding tothe growth of neurological disorders. Scientific studies have showed aclear relation between sleep-deprivation and the onset of Alzheimer'sand dementia. As an example, surgeons (having 24 hour shifts) developAlzheimer's around 10 years earlier than the general population. Similarresults are known for shift-workers and people with frequent exposure tojet-lag, and concerns extend to busy business people. The root cause ofthis is that during sleep, the brain naturally reduces toxic proteinsthat otherwise develop into plague and cause death of neurons that againleads to Alzheimer's and dementia.

Accordingly phototherapy systems and devices are provided herein thatare believed to be effective to induce and/or entrain brain oscillations(e.g., gamma oscillations) and thereby function in the prophylaxisand/or treatment of various neurological disorders. Additionally,methods of use of these devices and systems are provided.

Phototherapy Device

It was discovered that it is possible to provide a therapeutic lamp (orlamp system) (a phototherapy device) that modulates the neuron responsesin different parts of the brain (such as the hippocampus) withoutsubstantially affecting the vision of the subject (see, e.g. FIG. 1). Inparticular embodiments, the phototherapy device provides a blinkinglight effective to induce or entrain brain oscillations (e.g., gammaoscillations) and thereby improve cognition and/or prevent or mitigate aneurodegenerative disorder. It was discovered in studies investigatingthe brain response to blue and green light sources using functionalnuclear magnetic resonance imaging that the activity of the hippocampusis significantly increased in response to blue light as compared togreen light (see, e.g., Vandewalle et al. (2010) Proc. Natl. Acad. Sci.USA, 107: 19549-19554; and the like).

Exploiting this discovery, a phototherapy device was developed thatutilizes multiple wavelengths of illumination. In certain embodiments,particular wavelengths (e.g., spectral components) are selected tostimulate or entrain brain activity by administering them at a timevarying intensity (e.g., blinking), while other wavelengths are utilizedto mitigate adverse effects of the time-varying stimulation. Oneadvantage, inter alia, of using multiple wavelengths in the device isthat the brain response depends on the specific wavelengths and thiswavelength dependence is different from the wavelength sensitivity ofthe eye vision. The wavelength sensitivity of the receptors at theretina human (and other mammalian) vision is different from thewavelength sensitivity of the receptors (non-visual ganglion cells) thatcontrols hormone activity and the activity in the brain (e.g.,hippocampus).

The present inventors have therefore realized that it is possible todevelop a phototherapy device where modulation of the neuronal responsein the brain is obtained without substantially affecting the vision. Thesystem therefore provides an experience by a human's (or other mammal's)brain activity is modulated, but subject will not see theblinking/stroboscopic effect.

In certain embodiments this is accomplished by a phototherapy devicecomprising at least two providing two light sources. A first lightsource contains a blue light component” and the light source blinks at afrequency and intensity that induces or entrains brain oscillations in amammal. A second light source is provided that lack the blue component tor that contains the blue component at a substantially lower level thanthe blue component is the first light source. Despite the differentspectral composition of the first light source and the second lightsource, the spectral components are selected so that the illuminationproduced by the first light source and the second light source aresubstantially indistinguishable (e.g., in color) to the human (or othermammalian subject's) vision. FIGS. 3 and 6 show typical chromaticitydiagrams illustrating how a specific light color (e.g., white light) cangenerated with different wavelengths combinations. Typically, both thefirst and second light source will appear “white” although it will berecognized, and apparent from the chromaticity diagrams, that the lightsources can be operated to provide other colors.

Since at least the blue component of the first light source is blinking,and typically the entire first light source is blinking, to render theblinking substantially undetectable, the second light source is operatedin a blinking mode so it compensates for intensity changes in the firstlight source. Thus, for example, when the first light source decreasesin intensity, the second light source provides a corresponding increasein intensity. Conversely, when the first light source increases inintensity, the second light source provides a corresponding decrease inintensity. The result is that a blinking blue spectral component isproduced while the combined illumination (first and second light source)appears substantially constant in intensity and color.

Accordingly, in various embodiments a phototherapy device is providedthat delivers a blinking (flickering) illumination at a therapeuticintensity and wavelength (e.g., blue light component) where the blinkingis substantially undetectable by human vision even where the blinkfrequency is below the flicker fusion threshold. One such device isillustrated schematically in FIG. 1. As illustrated therein thephototherapy device 100 comprises a first light source 101 that producesa light that comprises or consists of a blue spectral component where atleast the blue spectral component (and all the illumination produced bythe first light source) is provided as a blinking light. Thephototherapy device also typically comprises a second source 102 thatproduces a light either substantially lacking a blue spectral component(e.g., substantially lacking a light component in the range of about 450nm to about 495 nm) or, where the second light produces a blue spectralcomponent, the blue spectral component produced by the second lightsource is smaller than the blue spectral component of the light producedby the first light source. Typically, the illumination produced by thesecond light source supplements the illumination produced by the firstlight source so that the blinking of the first light source whencombined with the light from said second light source is substantiallyundetectable by human vision, even where the blinking frequency is belowthe flicker fusion rate (e.g., below about 60 Hz).

In certain embodiments the blinking frequency and intensity of the firstlight source is sufficient to stimulate or to entrain brain waves in ahuman's brain when the human is exposed to said light source. In certainembodiments the stimulated or entrained brain waves comprise gammaoscillations.

A “gamma wave” or “gamma oscillation” is a pattern of neural oscillationin humans with a frequency between about 25 and about 100 Hz (Hughes(2008) Epilepsy Behav. 13(1): 25-31), though 40 Hz is typical (Gold(1999) Consciousness and Cognition, 8(2): 186-195). Gamma waves can beobserved as neural synchrony from visual cues in both conscious andsubliminal stimuli (see, e.g., Melloni et al. (2007) J. Neurosci.27(11): 2858-2865; Siegel et al. (2008) Neuron, 60(4): 709-719;Gregoriou et al. (2009) Science, 324(5931): 1207-1210; Baldauf et al.(2014) Science, 344(6182): 424-427; and the like). Gamma waves are alsoimplicated during rapid eye movement sleep and anesthesia, whichinvolves visualizations (see, e.g., Vanderwolf (2000) Brain Res. 855(2):217-224).

Without being bound to a particular theory, it is believed thatprovision of an appropriate blinking light can synchronize neuronactivity and it is believe this is beneficial to people with dementia orAlzheimer since the neuron activity will improve and lead to bettermemory and coordination of human activities. More specifically, it isbelieved the use of blinking illumination for the induction orentrainment of gamma oscillations can attenuates amyloid load and/ormodify microglia in the brain of a mammal. Accordingly, it is believedthe blinking light produced by the phototherapy devices described hereincan find utility in in the treatment and/or prevention of Alzheimer'sdisease, dementia, mild cognitive impairment (MCI), and relatedconditions. In this regard, FIG. 2 shows schematically how aphototherapy device or system, as described herein can use a blinkinglight source to stimulate neural activity to decrease amyloid plagueformation in the brain. The light therapy system provides light exposureto the ganglia cells in the eyes of a patient to stimulate brain waves,so-called gamma oscillations, in a manner in which the person is largelyundisturbed by the stroboscopic effect.

As noted above, in certain embodiments, the phototherapy devices use two(or more) light sources comprising different wavelengths, where a firstlight sources acts to stimulate the brain via stroboscopic (blinking)blue light or blue light component, and where a second light sourcesacts to supplement the first light source in such a manner that a humanbeing exposed to the combined light from the two sources does notexperience visual disadvantages by the stroboscopic (blinking) effect.As noted above, in certain embodiments the illumination produced by thesecond light source supplements the illumination produced by the firstlight source so that the blinking of the first light source whencombined with the light from said second light source is substantiallyundetectable by human vision, even where the blinking frequency is belowthe flicker fusion rate (e.g., below about 60 Hz).

More particularly, in certain embodiments, the phototherapy devicecomprises two light sources (e.g., two LED systems), a first lightsource and a second light source, (light sources 1 and 2, respectively),that have almost the same color temperatures. Typically, the first lightsource comprises or consists of a blue spectral component, produced, forexample, by a blue lamp (103 in FIG. 1), and at least the blue spectralcomponent is a blinking component. In certain embodiments all theillumination produced by the first light source is a blinkingillumination.

In certain embodiments the first light source produces light thatcomprises or consists of a blue spectral component, a green spectralcomponent, and an orange and/or red spectral component. In certainembodiments the first light source comprises or consists of a lamp thatemits primarily a blue light (103 in in the embodiment illustrated inFIG. 1), a lamp that emits primarily a green light (104 in in theembodiment illustrated in FIG. 1), and a lamp that emits primarily anorange and/or red light (105 in in the embodiment illustrated in FIG.1). Any of a number of lamps are suitable, however in certainembodiments the lamps comprise one or more LEDs.

FIG. 6, panel A, shows a chromaticity diagram for an illustrativeembodiment for the first light source. As shown, the first light sourcehas three colors with wavelengths (e.g., wavelength maxima) at 460 nm,550 nm, and 600 nm. The color coordinates are shown in the chromaticitydiagram in FIG. 6, panel A. As illustrated therein, the color mixing ofthe three colors leads to a white light source similar to a black bodyradiator with a color temperature of about 3000 K. This in indicated bythe black arrow in FIG. 6, panel A. In one illustrative, butnon-limiting embodiment see, e.g., FIG. 1) this can be achieved byproviding three different lamps (e.g., LEDs) in the first light source:One lamp 103 that produces a blue spectral component, one lamp 104 thatproduces a green spectral component, and one lamp 105 that produces ared and/or orange spectral component. It is noted that, while the firstlight source 101 is shown in FIG. 1 as containing three lamps, it willbe recognized the first light source and comprise or consist of more orfewer lamps. For example, multiple (e.g., 2, 3, 4, or more) lamps 103can be used to generate a blue spectral component, and/or multiple(e.g., 2, 3, 4, or more) lamps 104 can be used to generate a greenspectral component, and/or multiple (e.g., 2, 3, 4, or more) lamps 105can be used to generate an orange/red spectral component. Thus, asdesired, in certain embodiments, multiple lamps can be used to increasethe intensity of a particular spectral component. In certain embodimentstwo (or more) spectral components can be produced by a single lamp or bymultiple copies of a single lamp.

The second light source produces a light lacking a blue spectralcomponent or produces a blue spectral component that is smaller than theblue spectral component of the light produced by the first light source.In certain embodiments the second light source produces light thatcomprises or consists of a blue/green spectral component, an orangespectral component, and a red/far red spectral component, or the secondlight source produces light that completely lacks a blue spectralcomponent (e.g., that consists essentially of a green spectralcomponent, and an orange/red spectral component).

In certain embodiments, as illustrated in 6, panel B, the second lightsource can provide a light that is substantially lacking a blue spectralcomponent. In the embodiments illustrated in FIG. 1, and FIG. 6, panelB, the second light source produces a light that consists (or consistsessentially of green spectral component and an orange/red spectralcomponent).

In certain embodiments the second light source comprises or consists ofa lamp (e.g., 106 in FIG. 1) that emits primarily a green light (e.g.that produces primarily a green spectral component, and a lamp e.g., 107in FIG. 1) that emits primarily an orange and/or red light. It is notedthat, while the second light source 102 is shown in FIG. 1 as containingtwo lamps, it will be recognized the second light source can comprise orconsist of more or fewer lamps. For example, multiple (e.g., 2, 3, 4, ormore) lamps 106 can be used to generate a green spectral component,and/or multiple (e.g., 2, 3, 4, or more) lamps 107 can be used togenerate an orange and/or red spectral component. Thus, as desired, incertain embodiments, multiple lamps can be used to increase theintensity of a particular spectral component. In certain embodiments two(or more) spectral components can be produced by a single lamp or bymultiple copies of a single lamp.

Any of a number of lamps are suitable for use in the first light sourceand/or second light source. However, in various typical embodiments thelamps comprise one or more LEDs.

In the embodiment illustrated in FIG. 1, and FIG. 6, panel B, the secondlight source comprise two lamps (e.g., 2 LEDs) providing two spectralcomponents. Thus, the second light source can comprise LED(s) that emitat 500 nm and 610 nm, respectively, and the lamp will emit white lightwith a color temperature of 300 K+ΔT (see, e.g., FIG. 6, panel B).Looking directly into the two lamps with the human eye, the two lampsLED1 and LED2 will appear identical, or almost identical, if thefollowing four conditions are fulfilled:

-   -   1) The difference in correlated color temperatures ΔT between        the first light source and the second light source is small        (e.g., about 50K or less or about 30K, or about 20K or less, or        about 10K or less, or about 5K or less, or in certain        embodiments ranges from about 0.5K, or from about 1K or from        about 5K up to about 10K);    -   2) For each light source (light source 1 and light source 2) the        distance to the black-body locus D_(UV) is small (e.g., less        than about 0.01, or less than about 0.001, or less than about        0.0001);    -   3) The first light source and the second light source provide        illumination at approximately the same lux level (e.g., the        difference in intensity between the first light source and the        second light source is less than about 100 lux, or less than        about 75 lux, or less than about 50 lux, or less than about 40        lux, or less than about 30 lux, or less than about 20 lux, or        less than about 10 lux, or less than about 5 lux, or less than        about 2 lux); and    -   4) The first light source and the second light source emit light        in substantially the same direction (e.g., the difference in        illumination angel between the first light source and the second        light source is less than about 30 degrees, or less than about        25 degrees, or less than about 20 degrees, or less than about 15        degrees, or less than about 10 degrees, or less than about 5        degrees, about 1 degree or less).

In the example illustrated by FIG. 6, light source 1 (first lightsource) and light source 2 (second light source) consist of three andtwo colors. However, in general both light sources lamps can consist ofmany colors (more than 3 or 2). However, for maximum efficacy, it isdesired that ΔT be kept small and that that D_(uv) for each lamp issmall.

In another illustrative, but non-limiting embodiment, the first lightsource is an LED based light source (e.g., lamp) that comprises thewavelengths 460 nm (blue spectral component), 570 nm (green spectralcomponent), and 650 nm (red spectral component), and the second lightsource (e.g., lamp) is an LED based light source that comprises thewavelengths 490 nm (blue spectral component), 770 nm (far red spectralcomponent) (or 670 nm (red spectral component)) and 600 nm (orangespectral component).

As noted above, lamps that provide various spectral components in thefirst and/or second light source can comprise multiple lamps thatcontribute to a particular spectral component. It will be recognizedthat in certain embodiments, multiple lamps with different wavelengthprofiles may contribute to a “single” spectral component. Thus, forexample, a blue spectral component can be produced by the combination ofone lamp having a maximum emission at a wavelength of 460 nm and asecond lamp having a maximum emission at a wavelength of 480 nm. This isillustrative and non-limiting. Using the teaching provided herein, oneof skill in the art can routinely utilize one or more lamps to providelight sources suitable for use in the phototherapy devices describedherein.

The changes in intensity (and/or spectral composition) of the two lightsources (first light source and second light source) are substantiallysynchronized/coordinated such that intensity changes (and/or visiblecolor changes) in the first light source are compensated for byintensity changes (and/or visible color changes) in the second lightsource to provide a combined illumination that is substantially constant(e.g., flicker-free). Thus, as illustrated in FIG. 4A, which shows aschematic illustration of the alternating combination of the two lightsources, the light sources are modulated on-off 180 degrees out of phaseso that when the first light source is on, the second light source isoff. This is also illustrated by the power supply voltage for the twolight sources, e.g., LED1 and LED2 shown in FIG. 7. Again, the twovoltages are 180 degrees out of phase and therefore, when one of thelight sources is “on” the other light source is “off”. When the abovefour above conditions are fulfilled the two light sources have the samevisual appearance and when the lamps compensate for each other'sblinking, e.g., as explained above, the blinking will not be visible forthe human eye when illuminated by or looking into the phototherapydevice.

Accordingly, in certain embodiments the light sources (first lightsource and second light source) are operated out of phase so thatillumination provided by the second light source corrects for changes inillumination provided by the first light source thereby providingillumination that appears substantially constant to a subject (e.g., toa human or to a non-human mammal) even at a blink rate below the flickerfusion frequency for the subject.

In the illustrative examples shown in FIGS. 4A, 4B, and 6 the lightsources are modulated on-off (or high-low) and are essentially driven bya square wave voltage source. However, it will be recognized that thefirst light source and the second light source can be ramped up and downin gradual linear or non-linear manner. Thus, for example, FIG. 5 showsanother schematic illustration of alternating light sources, where thelight sources are modulated in a sinusoidal form. Accordingly, there areperiods where the light sources are emitting radiation at the same time,although at respective levels (at any given time) to produce a constanttotal illumination. In both examples, the total power emitted from thecombination of light sources is substantially uniform over time. Hence,the experience by a human is constant white light illumination, but thewhite light is composed of two different light sources of which oneprovides substantially more light, e.g., from 440 nm to 480 nm to thenon-visual ganglion cells at the retina and therefore increased brainactivity via stroboscopic light around 460 nm. It will be recognizedthat other wave forms for the illumination can be used. Such wave formsinclude, but are not limited to triangle, sawtooth, various non-linearwaveforms, and the like.

Particular in view of the various possible waveforms that can be used tofor the first and second light sources, the two sources need notnecessarily operate 180 degrees out of phase. Accordingly, in certainembodiments, the phase difference between the first light source and thesecond light source ranges from about 45 degrees, or from about 60degrees, or from about 75 degrees, or from about 90 degrees up to about180 degrees, or up to about 165 degrees, or up to about 150 degrees, orup to about 135 degrees. In certain embodiments the phase differencebetween the first light source and the second light source is about 180degrees so that when the first light source is on, the second lightsource is off and vice versa.

FIGS. 4A, 4B, and 6 illustrate the first light source and the secondlight source operating at a duty cycle of about 50%. Thus, for example,in one illustrative, but non-limiting embodiments the phototherapydevice uses an alternating combination of the light sources, at a 50%duty cycle at 40 HZ. Thus, the first light source comprising a bluespectral component (e.g., a 460 nm light) is stroboscopic at 40 HZ andthe second light source (e.g., that does not comprise light at 460 nm)is stroboscopic at 40 HZ. The two light sources are substantiallysynchronized such that when the first light source is turned on, thesecond light source is turned off, and vice versa.

However, alternative duty cycles are also contemplated. In certainembodiments the duty cycle of the first light source and/or the secondlight source ranges from about 5% up, or from about 10%, or from about15%, or from about 20%, or from about 25%, or from about 30%, or fromabout 35%, or from about 40% up to about 90%, or up to about 85%, or upto about 80%, or up to about 75%, or up to about 70%, or up to about65%, or up to about 60%. In certain embodiments the duty cycles of thefirst light source and the second light source are the same (e.g., incertain embodiments both light sources operate with a 50% duty cycle orone of the other duty cycles identified above). However, in otherembodiments the first light source and the second light source havedifferent duty cycles. Thus, for example, in certain embodiments theduty cycle of the first light source is 10% and the duty cycle of thesecond light source is 90% (e.g., a duty cycle ratio of 10:90). Otherduty cycle rations contemplated include, but are not limited to 5:95,25:75, 75:25, 95:5, and the like. In certain embodiments the ratio ofduty cycle of the first light source to the second light source rangesfrom about 1:10 to about 10:1, or from about 1:5 to about 5:1, or fromabout 1:2 to about 2:1, or is about 1:1.

As noted above, in various embodiments the blue spectral component ofthe second light source is lower than the blue spectral component of thefirst light source. In certain embodiments this is measured as theluminance at the wavelength of maximum intensity in the wavelength rangefrom about 450 nm to about 495 nm. In certain embodiments this ismeasured as the luminance integrated across the wavelength range fromabout 450 nm to about 495 nm. In certain embodiments the second lightsource luminance in the blue spectral component is less than about 60%,or less than about 50%, or less than about 40%, or less than about 30%,or less than about 20%, or less than about 10%, or less than about 5%,or less than about 3%, or less than about 2%, or less than about 1% thanthe luminance in the blue spectral component produced by the first lightsource. In certain embodiments the second light source provides noillumination in the blue spectral component (e.g., from about 450 nm toabout 495 nm).

It will be recognized by one of skill in the art that blinking of aspectral comment of the light or blinking of an entire light source neednot be an alternation between a full-on and a full-off condition. To thecontrary, such blinking can simply be a variation between a high state(e.g., bright light) and a low state (e.g., dim light), e.g., asillustrated in FIG. 4B.

In certain embodiments the frequency of blinking of the first lightsource (or spectral component thereof and/or the second light source (orspectral component thereof) ranges from about 20 Hz, or from about 30Hz, or from about 35 Hz or from about 40 Hz up to about 100 Hz, or up toabout 80 Hz, or up to about 60 Hz, or up to about 50 Hz, or up to about45 Hz. In certain embodiments the frequency of blinking of the firstlight source (or spectral component thereof and/or the second lightsource (or spectral component thereof) ranges from about 20 Hz up toabout 50 Hz. In certain embodiments the frequency of blinking of thefirst light source (or spectral component thereof and/or the secondlight source (or spectral component thereof) is about 40 Hz.

In certain embodiments the duration of the blinks of the first lightsource (or spectral component thereof) and/or the second light source(or spectral component thereof) ranges from about 1 ms, or from about 5ms up to about 50 ms, or up to about 40 ms, or up to about 30 ms, or upto about 20 ms, or up to about 15 ms, or up to about 10 ms. In certainembodiments the duration of the blinks of the first light source (orspectral component thereof) and/or the second light source (or spectralcomponent thereof) ranges from about 5 ms up to about 20 ms, or fromabout 8 ms up to about 15 ms.

In certain embodiments the color temperature of the first light sourceand/or second light source ranges from about 2700K, or from about 2800K,or from about 2900K up to about 6500K, or up to about 5000K, or up toabout 4000K, or up to about 3500K. In certain embodiments the colortemperature of the first light source and/or second light source rangesfrom about from about 2900K up to about 3100 K. In certain embodimentsthe color temperature of the first light source and/or second lightsource is about 3000K. As indicated above, in various embodiments, it isdesirable to keep the difference in correlated color temperatures ΔTbetween the first light source and the second light source small (e.g.,about 50K or less or about 30K, or about 20K or less, or about 10K orless, or about 5K or less, or in certain embodiments ranges from about0.5K, or from about 1K or from about 5K up to about 10K).

In certain embodiments the first light source and/or the second lightsource provides a luminous intensity ranging from about 10 lm, or fromabout 25 lm, or from about 50 lm, or from about 100 lm, or from about500 lm, up to about 10,000 lm, or up to about 5,000 lm, or up to about1000 lm.

In certain embodiments the first light source provides irradiance thatis larger than about 5 mW/nm/m² in a wavelength range from about 440 nmup to about 500 nm, or from about 450 nm up to about 490 nm, or fromabout 450 nm up to about 480 nm, or from about 450 nm up to about 470nm, or from about 455 nm up to about 465 nm.

In certain embodiments the first light source light has a totalilluminance and/or an illuminance of the blue spectral component of atleast about 10 lux, or at least about 20 lux, or at least about 30 lux,or at least about 40 lux, or at least about 50 lux, or at least about 60lux, or at least about 70 lux, or at least about 80 lux, or at leastabout 90 lux, or at least about 100 lux, or at least about 120 lux, orat least about 130 lux, or at least about 140 lux, or at least about 150lux, or at least about 160 lux, or at least about 170 lux, or at leastabout 180 lux, or at least about 190 lux, or at least about 200 lux, orat least about 300 lux, or at least about 400 lux, or at least about 500lux, or at least about 600 lux, or at least about 700 lux, or at leastabout 800 lux, or at least about 900 lux, or at least about 1000 lux.

In certain embodiments the second light source light has a totalilluminance of at least about 10 lux, or at least about 20 lux, or atleast about 30 lux, or at least about 40 lux, or at least about 50 lux,or at least about 60 lux, or at least about 70 lux, or at least about 80lux, or at least about 90 lux, or at least about 100 lux, or at leastabout 120 lux, or at least about 130 lux, or at least about 140 lux, orat least about 150 lux, or at least about 160 lux, or at least about 170lux, or at least about 180 lux, or at least about 190 lux, or at leastabout 200 lux, or at least about 300 lux, or at least about 400 lux, orat least about 500 lux, or at least about 600 lux, or at least about 700lux, or at least about 800 lux, or at least about 900 lux, or at leastabout 1000 lux.

In certain embodiments the distance to the black body locus DUV for thefirst light source and the second light source is less than about 0.01,or less than about 0.001, or less than about 0.0001. In certainembodiments the distance to the blackbody locus DUV for the first lightsource and the second light source is about 0.0001 or less.

In certain embodiments the difference in intensity between the firstlight source and the second light source is less than about 100 lux, orless than about 75 lux, or less than about 50 lux, or less than about 40lux, or less than about 30 lux, or less than about 20 lux, or less thanabout 10 lux, or less than about 5 lux, or less than about 2 lux.

In various embodiments illustrative, but non-limiting embodiments, thefirst light source and the second light source emit light insubstantially the same direction. In certain embodiments the differencein illumination angel between the first light source and the secondlight source is less than about 30 degrees, or less than about 25degrees, or less than about 20 degrees, or less than about 15 degrees,or less than about 10 degrees, or less than about 5 degrees, or lessthan about 3 degrees, or less than about 1 degree. In certainembodiments the co-alignment of illumination direct is accomplished byproviding the phototherapy device with a diffuser (see, e.g., 108 inFIG. 1, and image in FIG. 10) and/or a collimator.

In certain embodiments the light source comprises or consists of a bluespectral component, a green spectral component, and an orange or redspectral component. This can be accomplished, inter alia, by providingthe first light source with a lamp that emits primarily a blue light, alamp that emits primarily a green light, and a lamp that emits primarilyan orange and/or red light. In certain embodiments the blue lightcomprising the first light source, or the blue spectral component of thefirst light source, or the blue light emitted by a lamp is in thewavelength range from about 440 nm up to about 495 nm, or from about 440nm up to about 480 nm, or from about 450 nm up to about 480 nm, or fromabout 450 nm up to about 470 nm. In certain embodiments the blue lightcomprising the first light source, or the blue spectral component of thefirst light source, or the blue light emitted by a lamp has a maximumemission at about 460 nm.

In certain embodiments the green light comprising the first lightsource, or the green spectral component of the first light source, orthe green light emitted by a lamp comprising the second light source isprimarily in the wavelength range from about 495 nm up to about 570 nm,or from about 500 nm, or from about 510 nm, or from about 520 nm, orfrom about 530 nm, or from about 540 nm, or from about 550 nm up toabout 570 nm. This can be accomplished, inter alia, by providing thefirst light source with a lamp that emits primarily in the wavelengthrange from about 550 nm up to about 570 nm. In certain embodiments thegreen light comprising the first light source, or the green spectralcomponent of the first light source, or the green light emitted by alamp has a maximum emission at about 550 nm or at about 570 nm.

In certain embodiments the orange/red light comprising the first lightsource, or the orange/red spectral component of the first light source,or the orange/red light emitted by a lamp comprising the second lightsource is primarily in the wavelength range from about 590 nm up toabout 750 nm, or from about 600 nm up to about 700 nm, or up to about650 nm. In certain embodiments the orange/red light comprising the firstlight source, or the orange/red spectral component of the first lightsource, or the orange/red light emitted by a lamp is primarily in thewavelength range from about 600 nm up to about 650 nm. In certainembodiments the orange/red light comprising the first light source, orthe orange/red spectral component of the first light source, or theorange/red light emitted by a lamp has a maximum emission at about 600nm or at about 650 nm.

In certain embodiments the second light source comprises or consists ofa blue/green spectral component, an orange spectral component, and ared/far red spectral component; or the second light source comprises orconsists of a green spectral component, and an orange/red spectralcomponent. In certain embodiments the second light source comprises orconsists of a lamp that emits primarily a blue/green light, a lamp thatemits primarily an orange light, and a lamp that emits primarily ared/far red light; or the second light source comprises or consists of alamp that emits primarily a green light, and a lamp that emits primarilyan orange/red light.

In certain embodiments the second light source comprises or consists ofa lamp that emits primarily a blue/green light, a lamp that emitsprimarily an orange light, and a lamp that emits primarily a red/far redlight.

In certain embodiments the blue/green light comprising the second lightsource, or the blue/green spectral component of the second light source,or the blue/green light emitted by a lamp comprising the second lightsource is primarily in the wavelength range from about 490 nm up toabout 570 nm, or from about 500 nm, or from about 510 nm, or from about520 nm, or from about 530 nm, or from about 540 nm, or from about 550 nmup to about 570 nm. In certain embodiments the blue light comprising thesecond light source, or the blue spectral component of the second lightsource, or the blue light emitted by a lamp has a maximum emission atabout 490 nm.

In certain embodiments the orange light comprising the second lightsource, or the orange spectral component of the second light source, orthe orange light emitted by a lamp comprising the second light source isprimarily in the wavelength range from about 590 nm up to about 620 nm,or from about 590 nm up to about 610 nm. In certain embodiments theorange light comprising the second light source, or the orange spectralcomponent of the second light source, or the orange light emitted by alamp comprising the second light source has a maximum emission about 600nm.

In certain embodiments the red/far red light comprising the second lightsource, or the red/far red spectral component of the second lightsource, or the red/far red light emitted by a lamp comprising the secondlight source is primarily in the wavelength range from about 620 nm, upto about 770 nm, or from about 650 nm up to about 750 nm, or from about670 nm up to about 700 nm. In certain embodiments the the red/far redlight comprising the second light source, or the red/far red spectralcomponent of the second light source, or the red/far red light emittedby a lamp comprising the second light source is primarily is 670 nm orabout 770 nm.

In certain embodiments the second light source comprises or consists ofa lamp that emits primarily a green light, and a lamp that emitsprimarily an orange/red light. In certain embodiments the green lightcomprising the light emitted by the second light source, or the greenspectral component of the second light source, or the green lightemitted by a lamp comprising the second light source is primarily in thewavelength range from about 495 nm up to about 570 nm, or from about 500nm, or from about 510 nm, or from about 520 nm, or from about 530 nm, orfrom about 540 nm, or from about 550 nm up to about 570 nm. In certainembodiments the second light source, or the green spectral component ofthe second light source, or the green light emitted by a lamp isprimarily in the wavelength range from about 500nm up to about 550 nm.In certain embodiments the green light comprising the second lightsource, or the green spectral component of the second light source, orthe green light emitted by a lamp has a maximum emission at about 500nm. In certain embodiments the orange/red light comprising the secondlight source, or the orange/red spectral component of the second lightsource, or the orange/red light emitted by a lamp comprising the secondlight source is primarily in the wavelength range from about 590 nm upto about 750 nm, or from about 600 nm up to about 700 nm, or up to about650 nm. In certain embodiments the orange/red light comprising thesecond light source, or the orange/red spectral component of the secondlight source, or the orange/red light emitted by a lamp is primarily inthe wavelength range from about 600 nm up to about 650 nm. In certainembodiments the orange/red light comprising the second light source, orthe orange/red spectral component of the second light source, or theorange/red light emitted by a lamp has a maximum emission at about 600nm or at about 610 nm.

In certain embodiments the phototherapy devices described herein can beoperated in a colored mode. A specific color can be generated by themixing of different colors. For example, it is possible to generate ayellow color by the mixing of red light, e.g., at 630 nm and green lightat 530 nm (see, e.g., FIG. 11). The visual cortex in the brain willcombine the red color and the green color into a yellow color that willhave the same visual appearance for humans as a pure yellow color at 580nm (which is just in the middle of the interval from 530 nm to 630 nm).Thus, for example, it is possible to provide a yellow therapeutic lampthat oscillates between a first light source comprising a spectralcomponent at about 630 nm (red) and a spectral component at about 530 nm(green), and a second light source comprising a spectral component atabout 580 nm (yellow). Note that while hippocampal stimulation isreadily accomplished using a blue light, it is believed that hippocampalstimulation can also be accomplished using a flashing green light (or acombination of flashing blue and/or green lights). When the first lightsource and second light source are flashed out of phase, the blinking ofthe light at, for example, 40 Hz, will not be perceptible, however, itwill modulate the brain since 530 nm give a larger modulation in thehippo campus than 580 nm light. This principle may extended even furtherto incorporate blue light at, for example, about 470nm to about 480 nm,a wavelength range that is very effective for brain modulation relevantfor treatment of Alzheimer's. Thus, for example, in the chromaticitydiagram shown in FIG. 11 it is shown how the same yellow color made canbe made using a first light source comprising of blue at about 480 nmand yellow at about 575nm with a second light source providing colormixing of green at about 510 nm and red at about 600 nm. Thesecombinations are illustrative and non-limiting. Using the teachingprovided herein a phototherapy device comprising first light source(proving a blue and/or a green blinking component) and a second“complementary” light source that when combined with the light from saidfirst light source provides illumination in which the blinking issubstantially undetectable by human vision will be readily available toone of skill and capable of offering illumination in a variety ofcolors.

In certain embodiments the phototherapy device may comprise one or moreoptical elements, such as a diffuser, lenses, lens arrays, micro-lenses,micro-lens arrays, reflectors, diffractive optical elements, etc.,positioned in respective propagation paths of light emitted by the firstand/or second light sources for directing the emitted light into desireddirections.

Control Mechanism

In certain embodiments the light therapy devices described herein cancomprises a control mechanism (a controller, see, e.g., 110 in FIG. 1)that controls the emission spectrum from the first light source and/orthe second light source (e.g., a narrow and/or a broad spectrum lightsource). In certain embodiments the phototherapy device in combinationwith a controller and/or in combination with, e.g., a personalinformation device as described below, may comprise a light therapy(phototherapy) system.

In certain embodiments the controller may simply provide an on-offand/or brightness control (see, e.g., 112 in the illustrative, butnon-limiting embodiments shown in FIG. 1). However, in certainembodiments numerous other functions may be controlled. In certainembodiments illustrative controls can include one or more of thefollowing: on/off and/or brightness (112 FIG. 1), a blink frequencycontrol (113 FIG. 1), a phase and/or duty cycle control ((114 FIG. 1), acolor temperature and/or hue control (115 FIG. 1), and the like.

In certain embodiments the blinking blue light component (e.g., a narrowspectrum light source and/or first light source) emits for a shortertime period than the broad spectrum light source. In such embodiments,the brain is stimulated at certain times of the day or night to induceoscillations (e.g., gamma oscillations). As this may alter circadianrhythms of a person, it can be desirable to stimulate the brain only atcertain times of day, while providing constant illumination (without anoscillating component) at other times of the day or night.

The controller may also adjust the brightness and/or color temperatureof the phototherapy device in response to changes in ambient lightingconditions. Thus, for example during daylight hours the phototherapydevice may operate at higher intensities (brightens) than duringnighttime hours.

One illustrative, but non-limiting embodiment of control circuitry foroperating a light source comprising the phototherapy device describedherein is shown in FIG. 8 shows one illustrative, but non-limitingembodiment of a circuit that can drive a light source comprising aphototherapy device described herein. In one illustrative, butnon-limiting embodiment the phototherapy device comprises five LEDs thatform two different light sources (see, e.g., FIG. 1). In certainembodiments the driver electronics can be identical for each LED. Amicro-controller can provide signals to the “Dim” and “Enable” ports toenable the desired flickering and phase difference (e.g., 180 degreephase difference) between the two light sources. As an example of themicro-controller, in certain embodiments an Arduino MEGA2560micro-controller (see, e.g., FIG. 12) to generate the timing signals forthe LEDs, but other micro-controllers or computers can be used. FIG. 13illustrates the LEDs with mounts, driver electronics andmicro-controller all wired up. FIG. 14, provides a close-up view of theLEDs. It will be recognized that these embodiments are illustrative andnon-limiting. Using the teaching s provided herein, numerous variationsof controllers, control circuitry, light sources, and lamps will beavailable to one of skill in the art.

In this regard, it is noted that in certain embodiments the controlleris integral to the device (e.g., incorporated into the housing of thedevice), while in other embodiments, the controller may be remote fromthe device and coupled by a control cable or cables ((see, e.g., 109 inthe illustrative, but non-limiting embodiments shown in FIG. 1). Inother embodiments the controller may control the phototherapy devicethrough a radio link, a light (e.g., infra-red link), via a Bluetoothlink, and via a WiFi link. In certain embodiments the controllercomprises an App on a cell phone, tablet, or computer. Thus, in certainembodiment, the controller may be accommodated in a housing separatefrom the phototherapy device housing. For example, the controller mayreside in a separate room of a building comprising a plurality of rooms,each of which contains a phototherapy device controlled by thecontroller, e.g. in response to ambient light intensity, e.g., as sensedby one or more light sensors as described above and/or possibly, or inresponse to the time of day.

In certain embodiments the controller may be interconnected with one ormore phototherapy devices cables containing signal lines (see, e.g., 109in FIG. 1) for provision of control signals from the controller to thephototherapy device.

In certain embodiments the controller may be wirelessly interconnectedwith one or phototherapy device(s) for wireless transmission of controlsignals from the controller to the respective device(s). For example,the light controller and a phototherapy device may comprise an interfaceto a wired Local Area-Network (LAN) and/or to a wireless LAN (BlueTooth,WiFi), and/or a to a mobile telephone network, and/or to anotherWide-Area-Network (WAN), such as the internet. In this way networksalready present may be utilized for control of the phototherapy device.

Further, utilizing a LAN or a WAN, such as the Internet, makes itpossible for time keeping units and light sensors and other sensors anduser interfaces and the controller and other parts of the phototherapydevice/system to reside in separate locations possibly separated bylarge distances. For example, the controller software may reside on aserver, or may be distributed among a plurality of servers, connected tothe Internet and thus residing anywhere in the world in a location withInternet access.

In certain embodiments the phototherapy device/system may comprise ahand-held unit that is configured for connection to the phototherapydevice and has a user interface configured for user entry of user data,and where the hand-held unit is configured to transmit the user data tothe controller, and where the light controller is configured forcontrolling the phototherapy device in response to the user data.

In certain embodiments the hand-held unit may be a desktop computer, alaptop computer, a smartphone, a tablet, a wearable computer, such as asmartwatch, an activity tracker, etc., and may have an interface to aWired Local-Area Network (LAN) and/or a wireless LAN (BlueTooth, WiFi),and/or a mobile telephone network, and/or a Wide-Area-Network (WAN),such as the internet, and may be configured to be interconnected with aremote server through the network, e.g. for storage of data from sensorsof the hand-held unit, for entry of user data, etc.

Through the Wide-Area-Network, e.g. the Internet, the controller mayhave access to data, such as personal health data and/or electronic timemanagement and/or data provided by communication tools relating to andused by one or more users of the phototherapy device. In certainembodiments the tools and the stored information typically reside on oneor more remote servers accessed through the Wide-Area-Network. Incertain embodiments a plurality of devices, e.g. user's smartphones,with interfaces to the Wide-Area Network may access the one or moreremote servers through the Wide-Area-Network and may be used to enterinformation relating to the users.

The tools may Include electronic calendar system(s), email system(s),such as Microsoft Outlook, Windows Mail, Mozilla Thunderbird, AppleMail, Opera Mail, Hotmail, Gmail, etc., social network(s), professionalnetwork(s), such as Facebook®, LinkedIn®, Google+, Twitter, etc.,well-known for management of appointments and other daily activities andcommunications. Other tools include, but are not limited to web-basedhealth management systems hosted by a health care provider (e.g., aninsurance company, an HMO, etc.), or commercial internet healthmanagement services (e.g., Nokia/Withings, Internet Health Mgmt(®HealthMgmt), etc.).

In certain embodiments the controller, or a part of the controller, mayreside on a hand-held unit. A user interface for the phototherapy devicemay reside on a smartphone, and the smartphone may execute an appallowing the user to control the phototherapy device, e.g. foradjustment of one or more parameters, e.g., as described above.

In certain embodiments control (controller) software comprises means totake into account the individual's personal data, and preferablyquantified-self data from individual sensor(s) and/or tracker(s). Incertain embodiments the control software comprises means to take intoaccount the athlete's travel, training and competition program in orderto optimize training and/or performance at race events. In certainembodiments the control software runs semi- or fully-automatic withlittle or no interaction from the individual/user. In other embodiments,data collection of various parameters relevant for the individual isgathered using one or more sensors, for example in the form of awearable sensor.

In certain embodiments the system comprises an app-based interface, acloud-based database and means for analyzing individual data. In afurther preferred embodiment, the system comprises means for providingpersonal training advice/guidance. In certain embodiments the systemsand devices described herein are used by an athlete during trainingperiods and/or for competitions. It is an advantage that the systems anddevices described herein enable the athlete to optimize sleep duringintense training and/or competition programs. This is important as sleepis a critical parameter for recovery, and an athlete's reaction speedand ability to perform at maximum level.

Further, in certain embodiments the system uses an additional lightsource with stroboscopic effect to illuminate a human from above onhis/her head, whereby brain activity is increased.

Phototherapy Device Configurations

In certain embodiments the phototherapy devices described herein canadopt any of a number of configurations. Thus, for example, in certainembodiments, the phototherapy devices described herein comprises a lampor a luminaire, such as a lamp or luminaire positioned in a room, from aceiling, a stationary (standing) lamp, a desk lamp, a wall mounted lamp(e.g., a reading lamp), etc.).

In certain embodiments the phototherapy devices described herein operateover an extended time during a person's sleep. In certain embodimentsthe extended time is 1/2 hour or more, or about one hour or more, orabout 1.5 hours or more, or about 2 hours or more (for examplecontinuously over 1/2 hour or more, or about one hour or more, or about1.5 hours or more, or about 2 hours or more, or in multiple timesegments that total 1/2 hour or more, or about one hour or more, orabout 1.5 hours or more, or about 2 hours or more per night). In certainembodiments the phototherapy device comprises a sleep mask that providesa blinking blue spectral component, e.g., as described above. Thepresent inventors have further realized a method where a person is usingsuch a system, wherein the blinking blue light source illuminates aperson's eyelids during sleep. The system enables retinal ganglion cellsto be exposed be a fraction of the emitted stroboscopic blue light in asufficient time and intensity to positively affect or stimulate desiredparts of the brain.

In certain embodiments the phototherapy device(s) or the first and/orsecond light sources comprising the phototherapy devices describedherein may be configured for mounting proximate, or at, and/or attachedto, a frame of a window, for example attached to the frame of thewindow, the window being mounted in a wall of a room for daylightillumination of the room through the window pane.

In certain embodiments the proximity of the phototherapy devices or thefirst and/or second light sources comprising the phototherapy devicesfitting to the window, preferably the distance is less than 50 cm,preferred less than 25 cm, more preferred less than 10 cm, mostpreferred less than 5 cm, which causes the light emitted by thephototherapy device to be perceived as a part of the natural daylightilluminating the room through the window pane. In particular for elderlyor individuals in mentally challenged circumstances, the perception ofalienating or intruding technology may have a negative or sub-optimumeffect.

In certain embodiments the phototherapy device(s) or the first and/orsecond light sources comprising the phototherapy devices describedherein may be mounted so that the frame of the window is illuminated bythe phototherapy device(s) or the first and/or second light sourcescomprising the phototherapy devices described herein and the room isilluminated by light from the phototherapy device(s) or the first and/orsecond light sources comprising the phototherapy devices describedherein that has been reflected, e.g. diffusely reflected, into the roomby the frame of the window.

For example, the phototherapy device(s) or the first and/or second lightsources comprising the phototherapy devices described herein be mountedso that the light emitted by the light source is directed towards a partof the frame when the phototherapy device is mounted in its intendedposition for use, whereby light emitted by the phototherapy device isreflected by the frame of the window for illumination of the room incombination with sunlight entering the room through the Window pane. Theilluminated parts of the frame may be coated with a reflective materialfor improved illumination of the room.

In this manner a room may unobtrusively be administered a prophylacticor therapeutic light regimen as described herein.

In certain embodiments the phototherapy devices comprise a hardware parthaving one or more LED-based luminaires. Optionally, the system alsoincludes ceiling and/or table top luminaires. In certain embodiments thesystem may comprise head-mounted luminaires, for example light sourcesintegrated into sleep masks and/or glasses.

In certain embodiments the system is configured for use by individual(for example a patient, a prisoner, a student, an elderly individual ina private home, or an athlete) for optimizing rehabilitation, recovery,physiotherapy, practice, training and/or performance at competition.

In certain embodiments the phototherapy devices described herein areadapted to emit stroboscopic (blinking) light during morning hours, suchas from 6 am to 11 am, or a shorter time period within the morninghours. In certain embodiments the blue light source is emitting light ata predetermined time period defined by a user and/or defined by analgorithm. In certain embodiments the predefined algorithm may bedesigned to stabilize a human's circadian rhythm. The algorithm may bebased on machine-learning to tailored the stabilization via datacollected from a tracking device and/or personalized human data frome.g. DNA sequencing.

It is within the scope of the invention to combine a light therapysystem with non-invasive monitoring of activity, temperature, lightexposure, and other parameters, e.g., as described below. It is furtherwithin the scope to combine such embodiments with measurement ofsalivary hormone concentrations, and/or markers of amyloidogenicpathologies, and/or cognitive and behavioral functioning, in order toanalyze the consequences of the light exposure on circadian and mentalhealth.

Also within the scope of the present invention is the combination ofstroboscopic light (blinking light) as described herein with soundwaves. Examples of sound waves and light combinations for increasedbrain activity are described by Vandewalle et al. (2010) Proc. Natl.Acad. Sci. USA, 107: 19549-19554. A person skilled in the art of soundsystems would be able to combine sound waves into a system of thepresent invention.

In other preferred embodiments, a system according to the invention isused during treatment of cataracts. Such treatment can give more lightfrom 440 nm to 540 nm at the non-visual ganglion cells at the retina andtherefore increased brain activity via the stroboscopic light.

Personal Information/Tracking

In certain embodiments the phototherapy devices and/or controllersdescribed herein are configured with a personal information device intoa phototherapy system. Accordingly, in some embodiments, the systemfurther comprises a personal tracking device that records parametersincluding a person's body temperature, activity, movement, heart rate,blood pressure, and/or exposure to UV light.

Accordingly, in certain embodiments, the phototherapy system maycomprise one or more personal environment sensors configured to be wornby a human, e.g. selected from the group consisting of accelerometer,gyroscope, compass, ambient light sensor, UV sensor, GPS-unit, andbarometer, and wherein the phototherapy device controller is configuredfor controlling the phototherapy device in response to parameter valuesoutput by one or more personal environment sensors.

In certain embodiments the phototherapy device may, for example, beinterconnected with wearables used by a human, such as smart phones,smart watches, such as the Apple Watch, the Samsung Gear, the PebbleWatch, etc., activity trackers, such as the Fitbit Flex and others byFitbit, the Garmin Vivofit or others by Garmin, the Sony Smartband orothers by Sony, etc., etc., utilizing data from their sensors, typicallyincluding an ambient light sensor, GPS, an accelerometer, a clock, etc.

In certain embodiments the measured/recorded parameters are used toanalyze a person circadian rhythm and track their activity throughoutthe day using machine learning to personally optimize an individual'scircadian rhythm and/or to optimize the subject's cognitive performance.In certain embodiments the personal tracking device will further be ableto transmit information to a centralize cloud system that can then beutilized to detect any disruption in circadian rhythms and/or cognitiveperformance. In certain embodiments the cloud system can also beutilized to communicate with personal devices and automatically controllighting systems as a tool for personalized medicine.

In certain embodiments the tracking device uses a wireless connection,such as a blue tooth and or WIFI connection.

In certain embodiments the phototherapy device and/or controller has aninterface to a network and is configured to be interconnected with aremote server through the network for performing at least one of theoperations selected from the group consisting of utilizing computingresources of the remote server to control the light source, accesspersonal data relating to a human using the system, and access datarelating to the environment of the system.

In various preferred embodiments, the system is used for health careand/or improvements in life quality of elderly people; for improvementsin the performance of athletes (professionals as well as amateurs in abroad sense); for health care and/or improvements in life quality ofpeople spending the majority of their awake time indoors, such asimprisoned people; for improvements in sleeping pattern of children, aswell as for a number of other groups of people.

Multiple Devices and Combination Therapies

In certain embodiments the use of multiple phototherapy devicesdescribed herein is contemplated. For example, it is possible to usemultiple devices (such as in a private home, an office, at a hospitalroom, etc.), and the individual devices can be synchronized (in such amanner that the blinking of the first and second light sources arecontrolled to be substantially at the same timings). One advantage ofthis is that the multiple devices can act as an illumination system (forexample for general lighting) and at the same time, a person can betreated and/or exposed to light from multiple devices (without riskingthat the multiple devices cancel out each other, partly or fully).Another advantage is that multiple devices can be used to treat/expose aperson, and for example make it easier to treat an AD patient who isstruggling to be in one place for some time, or who is struggling tohave handle a device, or who is not able to operate a device. Hence, incertain embodiments, an automated system with multiple devices thatensure that the person receives the light therapy irrespective of howthe person is moving around, is contemplated.

Additionally, it is recognized that the phototherapy devices describedherein can be used in combination with other methods of neuralstimulation and/or with various pharmaceuticals (e.g., pharmaceuticalsfor use in the treatment of dementia and/or Alzheimer's disease). Thus,for example, in certain embodiments, the phototherapy devices and/orsystems described herein are used in combination with other means forneural stimulation, such as sound, physical vibration, electrical,transcranial magnetic stimulation, and the like.

In certain embodiments the phototherapy devices described herein areused in combination with treatment using various neuropharmaceuticals.Such neuropharmaceuticals include, but are not limited to,cholinesterase inhibitors such as donepezil (ARICEPT®), galantamine(RAZADYNE®), rivastigmine (EXELON®), and the like. Otherneuropharmaceuticals include, but are not limited to antipsychoticmedications for hallucinations, delusions, aggression, agitation,hostility, and/or uncooperativeness. Such medications include, but arenot limited to, aripiprazole (ABILIFY®), clozapine (CLOZARIL®),haloperidol (HALDOL®), olanzapine (ZYPREXA®), quetiapine (SEROQUEL®),risperidone (RISPERDAL®), ziprasidone (GEODON®), and the like.

Uses of Phototherapy Devices and Systems

The phototherapy devices and systems described herein can be for healthcare and/or improvements in life quality of elderly people, forimprovements in the performance of athletes (professionals as well asamateurs in a broad sense), for health care and/or improvements in lifequality of people spending the majority of their awake time indoors,such as imprisoned people; for improvements in sleeping pattern ofchildren, as well as for a number of other groups of people. Thephototherapy devices and systems described herein provide a lightingsystem for improved health care and/or life quality of an individual andcan be used for optimization of an individual's performance in amentally and/or physically demanding situation, such as a meeting, aperformance, a sports activity, a competition etc.

In various embodiments the phototherapy devices described herein arebelieved to be useful for the prophylaxis or treatment ofneurodegenerative disorders including, but not limited to Alzheimer'sdisease, mild cognitive impairment (MCI), depression, dementia,short-term memory, or for improved learning, improved athleticperformance or improved cognitive performance.

Increasing life expectancy, combined with the deterioration ofbiological processes with advancing age, necessitates the development oftechnologies that promote healthy aging. One often overlooked variablethat contributes markedly to age-related cognitive and somatic diseaseis the degradation of rhythmic biological functioning. Precise rhythmicpatterns of neural activity and physiological functioning are requiredfor optimal health and disease prevention. With advancing age, circadian(daily) rhythms degrade and the ability of the brain circadian clock tosynchronize to local time diminishes.

Consequently, aged individuals experience a loss of temporalcoordination among central and peripheral systems, accelerating theaging process and contributing to age-related disease and cognitivedecline. Specialized retinal ganglion cells sensitive to blue lightcommunicate directly to the brain's master circadian clock, making thesecells ideal targets to ameliorate age-related circadian decline. Inaddition, recent findings indicate an appropriate frequency of light(e.g., 40 Hz) can reverse the neural damage resulting from Alzheimer'sdisease in a mouse model (see, e.g., Iaccarino et al. (2016) Nature,540(8): 230-252).

Uses of the phototherapy devices and/or systems described hereinincludes elderly care with patients suffering from Alzheimer's disease.The phototherapy devices and/or systems described herein may beimplemented in elderly homes. The present invention will provideadditional advantages to the health care industry and addressAlzheimer's patients specifically.

In certain embodiments other embodiments, the phototherapy devicesand/or systems described herein are used during treatment of cataracts.

Uses of the phototherapy devices and/or systems described hereinincludes the sports and athlete domain. For example, a sport team mayuse the phototherapy devices and/or systems described herein in a mannerwhere the team acquires a set of phototherapy systems (one for eachindividual athlete on the team). The invention includes a service tocontrol the lighting for optimized lighting for the individual athletes.The invention further enables teams to quantify and predict potentialneural desynchronisis (such as from jetlag) and optimize recovery andsleep with respect to performance.

Professional sport teams suffer degraded performance due to disturbedcircadian rhythm and the present invention provides technologies and aservice to optimize sleep and recovery for the athletes. Thephototherapy devices and/or systems described herein further enableprediction of potentially long-term, harmful head injuries (such as mildor severe concussion) and aid the athlete in optimal recovery. Hence,the phototherapy devices and/or systems described herein can be used byathletes, such as swimmers, badminton, basketball, baseball, soccerplayers, etc.

Therapeutic and Prophylactic Methods

In various embodiments therapeutic and/or prophylactic methods areprovided that utilize the phototherapy devices and/or systems describedherein. Typically, the methods involve exposing a subject to a lightregimen described herein for a duration and intensity sufficient toinduce or entrain oscillatory brain activity (e.g., gamma oscillations)that have been shown to decrease AP.

Prophylaxis

In certain embodiments he phototherapy devices and/or systems describedherein are utilized in various prophylactic contexts. Thus, for example,in certain embodiments, the he phototherapy devices and/or systemsdescribed herein can be used to prevent or delay the onset of apre-Alzheimer's cognitive dysfunction, and/or to ameliorate one moresymptoms of a pre-Alzheimer's condition and/or cognitive dysfunction,and/or to prevent or delay the progression of a pre-Alzheimer'scondition and/or cognitive dysfunction to Alzheimer's disease.

Accordingly in certain embodiments, the prophylactic methods describedherein are contemplated for subjects identified as “at risk” and/or ashaving evidence of early Alzheimer's Disease (AD) pathological changes,but who do not meet clinical criteria for MCI or dementia. Without beingbound to a particular theory, it is believed that even this“preclinical” stage of the disease represents a continuum fromcompletely asymptomatic individuals with biomarker evidence suggestiveof AD-pathophysiological process(es) (abbreviated as AD-P, see, e.g.,Sperling et al. (2011) Alzheimer's & Dementia, 1-13) at risk forprogression to AD dementia to biomarker-positive individuals who arealready demonstrating very subtle decline but not yet meetingstandardized criteria for MCI (see, e.g., Albert et al. (2011)Alzheimer's and Dementia, 1-10 (doi:10.1016/j.jalz.2011.03.008).

This latter group of individuals might be classified as “not normal, notMCI” but would be can be designated “pre-symptomatic” or “pre-clinicalor “asymptomatic” or “premanifest”). In various embodiments thiscontinuum of pre-symptomatic AD can also encompass, but is notnecessarily limited to, (1) individuals who carry one or moreapolipoprotein E (APOE) ε4 alleles who are known or believed to have anincreased risk of developing AD dementia, at the point they are AD-Pbiomarker-positive, and (2) carriers of autosomal dominant mutations,who are in the presymptomatic biomarker-positive stage of their illness,and who will almost certainly manifest clinical symptoms and progress todementia.

A biomarker model has been proposed in which the most widely validatedbiomarkers of AD-P become abnormal and likewise reach a ceiling in anordered manner (see, e.g., Jack et al. (2010) Lancet Neurol., 9:119-128.). This biomarker model parallels proposed pathophysiologicalsequence of (pre-AD/AD), and is relevant to tracking the preclinical(asymptomatic) stages of AD (see, e.g., FIG. 3 in Sperling et al. (2011)Alzheimer's & Dementia, 1-13). Biomarkers of brain amyloidosis include,but are not limited to reductions in CSF Aβ₄₂ and increased amyloidtracer retention on positron emission tomography (PET) imaging. ElevatedCSF tau is not specific to AD and is thought to be a biomarker ofneuronal injury. Decreased fluorodeoxyglucose 18F (FDG) uptake on PETwith a temporoparietal pattern of hypometabolism is a biomarker ofAD-related synaptic dysfunction. Brain atrophy on structural magneticresonance imaging (MRI) in a characteristic pattern involving the medialtemporal lobes, paralimbic and temporoparietal cortices is a biomarkerof AD-related neurodegeneration. Other markers include, but are notlimited to volumetric MRI, FDG-PET, or plasma biomarkers (see, e.g.,Vemuri et al. (2009) Neurology, 73: 294-301; Yaffe et al. (2011) JAMA305: 261-266).

In certain embodiments the subjects suitable for the prophylacticmethods contemplated herein include, but are not limited to, subjectscharacterized as having asymptomatic cerebral amyloidosis. In variousembodiments these individuals have biomarker evidence of Aβ accumulationwith elevated tracer retention on PET amyloid imaging and/or low Aβ42 inCSF assay, but typically no detectable evidence of additional brainalterations suggestive of neurodegeneration or subtle cognitive and/orbehavioral symptomatology.

It is noted that currently available CSF and PET imaging biomarkers ofAP primarily provide evidence of amyloid accumulation and deposition offibrillar forms of amyloid. Data suggest that soluble or oligomericforms of AP are likely in equilibrium with plaques, which may serve asreservoirs. In certain embodiments it is contemplated that there is anidentifiable preplaque stage in which only soluble forms of AP arepresent. In certain embodiments it is contemplated that oligomeric formsof amyloid may be critical in the pathological cascade, and provideuseful markers. In addition, early synaptic changes may be presentbefore evidence of amyloid accumulation.

In certain embodiments the subjects suitable for the prophylacticmethods contemplated herein include, but are not limited to, subjectscharacterized as amyloid positive with evidence of synaptic dysfunctionand/or early neurodegeneration. In various embodiments these subjectshave evidence of amyloid positivity and presence of one or more markersof “downstream” AD-P-related neuronal injury. Illustrative, butnon-limiting markers of neuronal injury include, but are not limited to(1) elevated CSF tau or phospho-tau, (2) hypometabolism in an AD-likepattern (i.e., posterior cingulate, precuneus, and/or temporoparietalcortices) on FDG-PET, and (3) cortical thinning/gray matter loss in aspecific anatomic distribution (i.e., lateral and medial parietal,posterior cingulate, and lateral temporal cortices) and/or hippocampalatrophy on volumetric MRI. Other markers include, but are not limited tofMRI measures of default network connectivity. In certain embodimentsearly synaptic dysfunction, as assessed by functional imaging techniquessuch as FDG-PET and fMRI, can be detectable before volumetric loss.Without being bound to a particular theory, it is believed thatamyloid-positive individuals with evidence of early neurodegenerationmay be farther down the trajectory (i.e., in later stages of preclinical(asymptomatic) AD).

In certain embodiments the subjects suitable for the prophylacticmethods contemplated herein include, but are not limited to, subjectscharacterized as amyloid positive with evidence of neurodegeneration andsubtle cognitive decline. Without being bound to a particular theory, itis believed that those individuals with biomarker evidence of amyloidaccumulation, early neurodegeneration, and evidence of subtle cognitivedecline are in the last stage of preclinical (asymptomatic) AD, and areapproaching the border zone with clinical criteria for mild cognitiveimpairment (MCI). These individuals may demonstrate evidence of declinefrom their own baseline (particularly if proxies of cognitive reserveare taken into consideration), even if they still perform within the“normal” range on standard cognitive measures. Without being bound to aparticular theory, it is believed that more sensitive cognitivemeasures, particularly with challenging episodic memory measures, maydetect very subtle cognitive impairment in amyloid-positive individuals.In certain embodiments criteria include, but are not limited to,self-complaint of memory decline or other subtle neurobehavioralchanges.

As indicated above, subjects/patients amenable to prophylactic methodsdescribed herein include individuals at risk of disease (e.g., apathology characterized by amyloid plaque formation such as MCI) but notshowing symptoms, as well as subjects presently showing certain symptomsor markers. It is known that the risk of MCI and later Alzheimer'sdisease generally increases with age. Accordingly, in asymptomaticsubjects with no other known risk factors, in certain embodiments,prophylactic application is contemplated for subjects over 50 years ofage, or subjects over 55 years of age, or subjects over 60 years of age,or subjects over 65 years of age, or subjects over 70 years of age, orsubjects over 75 years of age, or subjects over 80 years of age, inparticular to prevent or slow the onset or ultimate severity of mildcognitive impairment (MCI), and/or to slow or prevent the progressionfrom MCI to early stage Alzheimer's disease (AD).

In certain embodiments, the methods described herein are especiallyuseful for individuals who do have a known genetic risk of Alzheimer'sdisease (or other amyloidogenic pathologies), whether they areasymptomatic or showing symptoms of disease. Such individuals includethose having relatives who have experienced MCI or AD (e.g., a parent, agrandparent, a sibling), and those whose risk is determined by analysisof genetic or biochemical markers. Genetic markers of risk towardAlzheimer's disease include, for example, mutations in the APP gene,particularly mutations at position 717 and positions 670 and 671referred to as the Hardy and Swedish mutations respectively (see Hardy(1997) Trends. Neurosci., 20: 154-159). Other markers of risk includemutations in the presenilin genes (PS1 and PS2), family history of AD,having the familial Alzheimer's disease (FAD) mutation, the APOE ε4allele, hypercholesterolemia or atherosclerosis. Further susceptibilitygenes for the development of Alzheimer's disease are reviewed, e.g., inSleegers, et al. (2010) Trends Genet. 26(2): 84-93.

In some embodiments, the subject is asymptomatic but has familial and/orgenetic risk factors for developing MCI or Alzheimer's disease. Inasymptomatic patients, treatment can begin at any age (e.g., at about20, about 30, about 40, about 50 years of age). Usually, however, it isnot necessary to begin treatment until a patient reaches at least about40, or at least about 50, or at least about 55, or at least about 60, orat least about 65, or at least about 70 years of age.

In some embodiments, the subject exhibits symptoms, for example, of mildcognitive impairment (MCI) or Alzheimer's disease (AD). Individualspresently suffering from Alzheimer's disease can be recognized fromcharacteristic dementia, as well as the presence of risk factorsdescribed above. In addition, a number of diagnostic tests are availablefor identifying individuals who have AD. These include measurement ofCSF Tau, phospho-tau (pTau), Aβ42 levels and C-terminally cleaved APPfragment (APPneo). Elevated total-Tau (tTau), phospho-Tau (pTau),APPneo, soluble Aβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and decreasedAβ42 levels, Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα levels, sAPPα/sAPPβratio, sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio signify the presence ofAD. In some embodiments, the subject or patient is diagnosed as havingMCI. Increased levels of neural thread protein (NTP) in urine and/orincreased levels of α2-macroglobulin (α2M) and/or complement factor H(CFH) in plasma are also biomarkers of MCI and/or AD (see, e.g., Anoopet al. (2010) Int. J. Alzheimer's Dis. 2010:606802).

In certain embodiments, subjects amenable to treatment may haveage-associated memory impairment (AAMI), or mild cognitive impairment(MCI). The methods described herein are particularly well-suited to theprophylaxis and/or treatment of MCI. In such instances, the methods candelay or prevent the onset of MCI, and or reduce one or more symptomscharacteristic of MCI and/or delay or prevent the progression from MCIto early-, mid- or late-stage Alzheimer's disease or reduce the ultimateseverity of the disease.

Mild Cognitive Impairment (MCI)

Mild cognitive impairment (MCI, also known as incipient dementia, orisolated memory impairment) is a diagnosis given to individuals who havecognitive impairments beyond that expected for their age and education,but that typically do not interfere significantly with their dailyactivities (see, e.g., Petersen et al. (1999) Arch. Neurol. 56(3):303-308). It is considered in many instances to be a boundary ortransitional stage between normal aging and dementia. Although MCI canpresent with a variety of symptoms, when memory loss is the predominantsymptom it is termed “amnestic MCI” and is frequently seen as a riskfactor for Alzheimer's disease (see, e.g., Grundman et al. (2004) Arch.Neurol. 61(1): 59-66; and on the interne aten.wikipedia.org/wiki/Mild_cognitive_impairment-cite_note-Grundman-1).When individuals have impairments in domains other than memory it isoften classified as non-amnestic single- or multiple-domain MCI andthese individuals are believed to be more likely to convert to otherdementias (e.g., dementia with Lewy bodies). There is evidencesuggesting that while amnestic MCI patients may not meet neuropathologiccriteria for Alzheimer's disease, patients may be in a transitionalstage of evolving Alzheimer's disease; patients in this hypothesizedtransitional stage demonstrated diffuse amyloid in the neocortex andfrequent neurofibrillary tangles in the medial temporal lobe (see, e.g.,Petersen et al. (2006) Arch. Neurol. 63(5): 665-72).

The diagnosis of MCI typically involves a comprehensive clinicalassessment including clinical observation, neuroimaging, blood tests andneuropsychological testing. In certain embodiments diagnostic criteriafor MIC include, but are not limited to those described by Albert et al.(2011) Alzheimer's & Dementia. 1-10. As described therein, diagnosticcriteria include (1) core clinical criteria that could be used byhealthcare providers without access to advanced imaging techniques orcerebrospinal fluid analysis, and (2) research criteria that could beused in clinical research settings, including clinical trials. Thesecond set of criteria incorporate the use of biomarkers based onimaging and cerebrospinal fluid measures. The final set of criteria formild cognitive impairment due to AD has four levels of certainty,depending on the presence and nature of the biomarker findings.

In certain embodiments clinical evaluation/diagnosis of MCI involves:(1) Concern reflecting a change in cognition reported by patient orinformant or clinician (i.e., historical or observed evidence of declineover time); (2) Objective evidence of Impairment in one or morecognitive domains, typically including memory (i.e., formal or bedsidetesting to establish level of cognitive function in multiple domains);(3) Preservation of independence in functional abilities; (4) Notdemented; and in certain embodiments, (5) An etiology of MCI consistentwith AD pathophysiological processes. Typically, vascular, traumatic,and medical causes of cognitive decline, are ruled out where possible.In certain embodiments, when feasible, evidence of longitudinal declinein cognition is identified. Diagnosis is reinforced by a historyconsistent with AD genetic factors, where relevant.

With respect to impairment in cognitive domain(s), there should beevidence of concern about a change in cognition, in comparison with theperson's previous level. There should be evidence of lower performancein one or more cognitive domains that is greater than would be expectedfor the patient's age and educational background. If repeatedassessments are available, then a decline in performance should beevident over time. This change can occur in a variety of cognitivedomains, including memory, executive function, attention, language, andvisuospatial skills. An impairment in episodic memory (i.e., the abilityto learn and retain new information) is seen most commonly in MCIpatients who subsequently progress to a diagnosis of AD dementia.

With respect to preservation of independence in functional abilities, itis noted that persons with MCI commonly have mild problems performingcomplex functional tasks which they used to perform shopping. They maytake more time, be less efficient, and make more errors at performingsuch activities than in the past. Nevertheless, they generally maintaintheir independence of function in daily life, with minimal aids orassistance.

With respect to dementia, the cognitive changes should be sufficientlymild that there is no evidence of a significant impairment in social oroccupational functioning. If an individual has only been evaluated once,change will be inferred from the history and/or evidence that cognitiveperformance is impaired beyond what would have been expected for thatindividual.

Cognitive testing is optimal for objectively assessing the degree ofcognitive impairment for an individual. Scores on cognitive tests forindividuals with MCI are typically 1 to 1.5 standard deviations belowthe mean for their age and education matched peers on culturallyappropriate normative data (i.e., for the impaired domain(s), whenavailable).

Episodic memory (i.e., the ability to learn and retain new information)is most commonly seen in MCI patients who subsequently progress to adiagnosis of AD dementia. There are a variety of episodic memory teststhat are useful for identifying those MCI patients who have a highlikelihood of progressing to AD dementia within a few years. These teststypically assess both immediate and delayed recall, so that it ispossible to determine retention over a delay. Many, although not all, ofthe tests that have proven useful in this regard are wordlist learningtests with multiple trials. Such tests reveal the rate of learning overtime, as well as the maximum amount acquired over the course of thelearning trials. They are also useful for demonstrating that theindividual is, in fact, paying attention to the task on immediaterecall, which then can be used as a baseline to assess the relativeamount of material retained on delayed recall. Examples of such testsinclude (but are not limited to: the Free and Cued Selective RemindingTest, the Rey Auditory Verbal Learning Test, and the California VerbalLearning Test. Other episodic memory measures include, but are notlimited to: immediate and delayed recall of a paragraph such as theLogical Memory I and II of the Wechsler Memory Scale Revised (or otherversions) and immediate and delayed recall of nonverbal materials, suchas the Visual Reproduction subtests of the Wechsler Memory Scale-RevisedI and II.

Because other cognitive domains can be impaired among individuals withMCI, it is desirable to examine domains in addition to memory. Theseinclude, but are not limited to executive functions (e.g., set-shifting,reasoning, problem-solving, planning), language (e.g., naming, fluency,expressive speech, and comprehension), visuospatial skills, andattentional control (e.g., simple and divided attention). Many clinicalneuropsychological measures are available to assess these cognitivedomains, including (but not limited to the Trail Making Test (executivefunction), the Boston Naming Test, letter and category fluency(language), figure copying (spatial skills), and digit span forward(attention).

As indicated above, genetic factors can be incorporated into thediagnosis of MCI. If an autosomal dominant form of AD is known to bepresent (i.e., mutation in APP, PS1, PS2), then the development of MCIis most likely the precursor to AD dementia. The large majority of thesecases develop early onset AD (i.e., onset below 65 years of age).

In addition, there are genetic influences on the development of lateonset AD dementia. For example, the presence of one or two ε4 alleles inthe apolipoprotein E (APOE) gene is a genetic variant broadly acceptedas increasing risk for late-onset AD dementia. Evidence suggests that anindividual who meets the clinical, cognitive, and etiologic criteria forMCI, and is also APOE ε4 positive, is more likely to progress to ADdementia within a few years than an individual without this geneticcharacteristic. It is believed that additional genes play an important,but smaller role than APOE and also confer changes in risk forprogression to AD dementia (see, e.g., Bertram et al. (2010) Neuron, 21:270-281).

In certain embodiments subjects suitable for the prophylactic methodsdescribed herein include, but need not be limited to, subjectsidentified having one or more of the core clinical criteria describedabove and/or subjects identified with one or more “research criteria”for MCI, e.g., as described below.

“Research criteria” for the identification/prognosis of MCI include, butare not limited to biomarkers that increase the likelihood that MCIsyndrome is due to the pathophysiological processes of AD. Without beingbound to a particular theory, it is believed that the conjointapplication of clinical criteria and biomarkers can result in variouslevels of certainty that the MCI syndrome is due to ADpathophysiological processes. In certain embodiments, two categories ofbiomarkers have been the most studied and applied to clinical outcomesare contemplated. These include “Aβ” (which includes CSF Aβ₄₂ and/or PETamyloid imaging) and “biomarkers of neuronal injury” (which include, butare not limited to CSF tau/p-tau, hippocampal, or medial temporal lobeatrophy on MRI, and temporoparietal/precuneus hypometabolism orhypoperfusion on PET or SPECT).

Without being bound to a particular theory, it is believed that evidenceof both AP, and neuronal injury (either an increase in tau/p-tau orimaging biomarkers in a topographical pattern characteristic of AD),together confers the highest probability that the AD pathophysiologicalprocess is present. Conversely, if these biomarkers are negative, thismay provide information concerning the likelihood of an alternatediagnosis. It is recognized that biomarker findings may be contradictoryand accordingly any biomarker combination is indicative (an indicator)used on the context of a differential diagnosis and not itselfdispositive. It is recognized that varying severities of an abnormalitymay confer different likelihoods or prognoses, that are difficult toquantify accurately for broad application.

For those potential MCI subjects whose clinical and cognitive MCIsyndrome is consistent with AD as the etiology, the addition ofbiomarker analysis effects levels of certainty in the diagnosis. In themost typical example in which the clinical and cognitive syndrome of MCIhas been established, including evidence of an episodic memory disorderand a presumed degenerative etiology, the most likely cause is theneurodegenerative process of AD. However, the eventual outcome still hasvariable degrees of certainty. The likelihood of progression to ADdementia will vary with the severity of the cognitive decline and thenature of the evidence suggesting that AD pathophysiology is theunderlying cause. Without being bound to a particular theory it isbelieved that positive biomarkers reflecting neuronal injury increasethe likelihood that progression to dementia will occur within a fewyears and that positive findings reflecting both Aβ accumulation andneuronal injury together confer the highest likelihood that thediagnosis is MCI due to AD.

A positive Aβ biomarker and a positive biomarker of neuronal injuryprovide an indication that the MCI syndrome is due to AD processes andthe subject is well suited for the methods described herein.

A positive Aβ biomarker in a situation in which neuronal injurybiomarkers have not been or cannot be tested or a positive biomarker ofneuronal injury in a situation in which Aβ biomarkers have not been orcannot be tested indicate an intermediate likelihood that the MCIsyndrome is due to AD. Such subjects are believed to be is well suitedfor the methods described herein

Negative biomarkers for both Aβ and neuronal injury suggest that the MCIsyndrome is not due to AD. In such instances the subjects may not bewell suited for the methods described herein.

There is evidence that magnetic resonance imaging can observedeterioration, including progressive loss of gray matter in the brain,from mild cognitive impairment to full-blown Alzheimer disease (see,e.g., Whitwell et al. (2008) Neurology 70(7): 512-520). A techniqueknown as PiB PET imaging is used to clearly show the sites and shapes ofbeta amyloid deposits in living subjects using a C11 tracer that bindsselectively to such deposits (see, e.g., Jack et al. (2008) Brain 131(Pt3): 665-680).

In certain embodiments, MCI is typically diagnosed when there is 1)Evidence of memory impairment; 2) Preservation of general cognitive andfunctional abilities; and 3) Absence of diagnosed dementia.

In certain embodiments MCI and stages of Alzheimer's disease can beidentified/categorized, in part by Clinical Dementia Rating (CDR)scores. The CDR is a five point scale used to characterize six domainsof cognitive and functional performance applicable to Alzheimer diseaseand related dementias: Memory, Orientation, Judgment & Problem Solving,Community Affairs, Home & Hobbies, and Personal Care. The information tomake each rating can be obtained through a semi-structured interview ofthe patient and a reliable informant or collateral source (e.g., familymember).

The CDR table provides descriptive anchors that guide the clinician inmaking appropriate ratings based on interview data and clinicaljudgment. In addition to ratings for each domain, an overall CDR scoremay be calculated through the use of an algorithm. This score is usefulfor characterizing and tracking a patient's level ofimpairment/dementia: 0=Normal; 0.5=Very Mild Dementia; 1=Mild Dementia;2=Moderate Dementia; and 3=Severe Dementia. An illustrative CDR table isshown in Table 2.

TABLE 2 Illustrative clinical dementia rating (CDR) table. Impairment:None Questionable Mild Moderate Severe CDR: 0 0.5 1 2 3 Memory No memoryConsistent Moderate Severe Severe loss or slight memory loss; memorymemory slight forgetfulness; more marked loss; only loss; onlyinconsistent partial for recent highly fragments forgetfulnessrecollection events; learned remain of events' defect material “benign”interferes retained; forgetfulness with new material everyday rapidlylost activities Orientation Fully Fully Moderate Severe Oriented tooriented oriented difficulty difficulty person only except for with timewith time slight relationships; relationships; difficulty oriented forusually with time place at disoriented relationships examination; totime, may have often to geographic place. disorientation elsewhereJudgment & Solves Slight Moderate Severely Unable to Problem everydayimpairment difficulty in impaired in make Solving problems & in solvinghandling handling judgments handles problems, problems, problems, orsolve business & similarities, similarities similarities problemsfinancial and and and affairs well; differences differences;differences; judgment social social good in judgment judgment relationto usually usually past maintained impaired performance CommunityIndependent Slight Unable to No pretense of independent Affairs functionat impairment function function outside of home usual level in theseindependently Appears Appears too in job, activities at these wellenough ill to be shopping, activities to be taken taken to volunteer,although may to functions functions and social still be outside aoutside a groups engaged in family home family some; home. appearsnormal to casual inspection Home and Life at Life at home, Mild bit Onlysimple No Hobbies home, hobbies, and definite chores significanthobbies, and intellectual impairment preserved; function in intellectualinterests of function at very home interests slightly home; morerestricted well impaired difficult interests, maintained chores poorlyabandoned; maintained more complicated hobbies and interests abandonedPersonal Fully capable of self-care Needs Requires Requires Careprompting assistance in much help dressing, with hygiene, personalkeeping of care; personal frequent effects incontinence

A CDR rating of ˜0.5 or ˜0.5 to 1.0 is often considered clinicallyrelevant MCI. Higher CDR ratings can be indicative of progression intoAlzheimer's disease.

In certain embodiments use of the phototherapy devices and/or systemsdescribed herein is deemed effective when there is a reduction in theCSF of levels of one or more components selected from the groupconsisting of Tau, phospho-Tau (pTau), APPneo, soluble Aβ40, solubleAβ42, and/or Aβ42/Aβ40 ratio, and/or when there is a reduction of theplaque load in the brain of the subject, and/or when there is areduction in the rate of plaque formation in the brain of the subject,and/or when there is an improvement in the cognitive abilities of thesubject, and/or when there is a perceived improvement in quality of lifeby the subject, and/or when there is a significant reduction in clinicaldementia rating (CDR), and/or when the rate of increase in clinicaldementia rating is slowed or stopped and/or when the progression fromMCI to early stage AD is slowed or stopped.

In some embodiments, a diagnosis of MCI can be determined by consideringthe results of several clinical tests. For example, Grundman, et al.(2004) Arch Neurol 61: 59-66, report that a diagnosis of MCI can beestablished with clinical efficiency using a simple memory test(paragraph recall) to establish an objective memory deficit, a measureof general cognition (Mini-Mental State Exam (MMSE), discussed ingreater detail below) to exclude a broader cognitive decline beyondmemory, and a structured clinical interview (CDR) with patients andcaregivers to verify the patient's memory complaint and memory loss andto ensure that the patient was not demented. Patients with MCI perform,on average, less than 1 standard deviation (SD) below normal onnonmemorycognitive measures included in the battery. Tests of learning,attention, perceptual speed, category fluency, and executive functionmay be impaired in patients with MCI, but these are far less prominentthan the memory deficit.

Alzheimer's Disease (AD)

In certain embodiments the phototherapy devices and/or systems describedherein are contemplated for the treatment of Alzheimer's disease. Insuch instances the methods described herein are useful in preventing orslowing the onset of Alzheimer's disease (AD), in reducing the severityof AD when the subject has transitioned to clinical AD diagnosis, and/orin mitigating one or more symptoms of Alzheimer's disease.

In particular, where the Alzheimer's disease is early stage, it isbelieved the methods can reduce or eliminate one or more symptomscharacteristic of AD and/or delay or prevent the progression from MCI toearly or later stage Alzheimer's disease.

Individuals presently suffering from Alzheimer's disease can berecognized from characteristic dementia, as well as the presence of riskfactors described above. In addition, a number of diagnostic tests areavailable for identifying individuals who have AD. Individuals presentlysuffering from Alzheimer's disease can be recognized from characteristicdementia, as well as the presence of risk factors described above. Inaddition, a number of diagnostic tests are available for identifyingindividuals who have AD. These include measurement of CSF Tau,phospho-tau (pTau), sAPPα, sAPPβ, Aβ40, Aβ42 levels and/or C terminallycleaved APP fragment (APPneo). Elevated Tau, pTau, sAPPβ and/or APPneo,and/or decreased sAPPα, soluble Aβ40 and/or soluble Aβ42 levels,particularly in the context of a differential diagnosis, can signify thepresence of AD.

In certain embodiments subjects amenable to treatment may haveAlzheimer's disease. Individuals suffering from Alzheimer's disease canalso be diagnosed by Alzheimer's disease and Related DisordersAssociation (ADRDA) criteria. The NINCDS-ADRDA Alzheimer's Criteria wereproposed in 1984 by the National Institute of Neurological andCommunicative Disorders and Stroke and the Alzheimer's Disease andRelated Disorders Association (now known as the Alzheimer's Association)and are among the most used in the diagnosis of Alzheimer's disease(AD). McKhann, et al. (1984) Neurology 34(7): 939-44. According to thesecriteria, the presence of cognitive impairment and a suspected dementiasyndrome should be confirmed by neuropsychological testing for aclinical diagnosis of possible or probable AD. However, histopathologicconfirmation (microscopic examination of brain tissue) is generally usedfor a dispositive diagnosis. The NINCDS-ADRDA Alzheimer's Criteriaspecify eight cognitive domains that may be impaired in AD: memory,language, perceptual skills, attention, constructive abilities,orientation, problem solving and functional abilities). These criteriahave shown good reliability and validity.

Baseline evaluations of patient function can made using classicpsychometric measures, such as the Mini-Mental State Exam (MMSE)(Folstein et al. (1975) J. Psychiatric Research 12 (3): 189-198), andthe Alzheimer's Disease Assessment Scale (ADAS), which is acomprehensive scale for evaluating patients with Alzheimer's Diseasestatus and function (see, e.g., Rosen, et al. (1984) Am. J. Psychiatr.,141: 1356-1364). These psychometric scales provide a measure ofprogression of the Alzheimer's condition. Suitable qualitative lifescales can also be used to monitor treatment. The extent of diseaseprogression can be determined using a Mini-Mental State Exam (MMSE)(see, e.g., Folstein, et al. supra). Any score greater than or equal to25 points (out of 30) is effectively normal (intact). Below this, scorescan indicate severe (≤9 points), moderate (10-20 points) or mild (21-24points) Alzheimer's disease.

Alzheimer's disease can be broken down into various stages including: 1)Moderate cognitive decline (Mild or early-stage Alzheimer's disease), 2)Moderately severe cognitive decline (Moderate or mid-stage Alzheimer'sdisease), 3) Severe cognitive decline (Moderately severe or mid-stageAlzheimer's disease), and 4) Very severe cognitive decline (Severe orlate-stage Alzheimer's disease) as shown in Table 3.

TABLE 3 Illustrative stages of Alzheimer's disease. Moderate CognitiveDecline (Mild or early stage AD) At this stage, a careful medicalinterview detects clear-cut deficiencies in the following areas:Decreased knowledge of recent events. Impaired ability to performchallenging mental arithmetic. For example, to count backward from 100by 7s. Decreased capacity to perform complex tasks, such as marketing,planning dinner for guests, or paying bills and managing finances.Reduced memory of personal history. The affected individual may seemsubdued and withdrawn, especially in socially or mentally challengingsituations. Moderately severe cognitive decline (Moderate or mid-stageAlzheimer's disease) Major gaps in memory and deficits in cognitivefunction emerge. Some assistance with day-to-day activities becomesessential. At this stage, individuals may: Be unable during a medicalinterview to recall such important details as their current address,their telephone number, or the name of the college or high school fromwhich they graduated. Become confused about where they are or about thedate, day of the week or season. Have trouble with less challengingmental arithmetic; for example, counting backward from 40 by 4s or from20 by 2s. Need help choosing proper clothing for the season or theoccasion. Usually retain substantial knowledge about themselves and knowtheir own name and the names of their spouse or children. Usuallyrequire no assistance with eating or using the toilet. Severe cognitivedecline (Moderately severe or mid-stage Alzheimer's disease) Memorydifficulties continue to worsen, significant personality changes mayemerge, and affected individuals need extensive help with dailyactivities. At this stage, individuals may: Lose most awareness ofrecent experiences and events as well as of their surroundings.Recollect their personal history imperfectly, although they generallyrecall their own name. Occasionally forget the name of their spouse orprimary caregiver but generally can distinguish familiar from unfamiliarfaces. Need help getting dressed properly; without supervision, may makesuch errors as putting pajamas over daytime clothes or shoes on wrongfeet. Experience disruption of their normal sleep/waking cycle. Needhelp with handling details of toileting (flushing toilet, wiping anddisposing of tissue properly). Have increasing episodes of urinary orfecal incontinence. Experience significant personality changes andbehavioral symptoms, including suspiciousness and delusions (forexample, believing that their caregiver is an impostor); hallucinations(seeing or hearing things that are not really there); or compulsive,repetitive behaviors such as hand- wringing or tissue shredding. Tend towander and become lost. Very severe cognitive decline (Severe orlate-stage Alzheimer's disease) This is the final stage of the diseasewhen individuals lose the ability to respond to their environment, theability to speak, and, ultimately, the ability to control movement.Frequently individuals lose their capacity for recognizable speech,although words or phrases may occasionally be uttered. Individuals needhelp with eating and toileting and there is general incontinence.Individuals lose the ability to walk without assistance, then theability to sit without support, the ability to smile, and the ability tohold their head up. Reflexes become abnormal and muscles grow rigid.Swallowing is impaired.

In various embodiments the use of the phototherapy devices and/orsystems described herein is deemed effective when the there is areduction in the CSF of levels of one or more components selected fromthe group consisting of Tau, phospho-Tau (pTau), APPneo, soluble Aβ40,soluble Aβ42, and/or and Aβ42/Aβ40 ratio, and/or when there is areduction of the plaque load in the brain of the subject, and/or whenthere is a reduction in the rate of plaque formation in the brain of thesubject, and/or when there is an improvement in the cognitive abilitiesof the subject, and/or when there is a perceived improvement in qualityof life by the subject, and/or when there is a significant reduction inclinical dementia rating (CDR) of the subject, and/or when the rate ofincrease in clinical dementia rating is slowed or stopped and/or whenthe progression of AD is slowed or stopped (e.g., when the transitionfrom one stage to another as listed in Table 3 is slowed or stopped).

In certain embodiments subjects amenable to the present methodsgenerally are free of a neurological disease or disorder other thanAlzheimer's disease. For example, in certain embodiments, the subjectdoes not have and is not at risk of developing a neurological disease ordisorder such as Parkinson's disease, and/or schizophrenia, and/orpsychosis.

The foregoing uses are illustrative and non-limiting. Using the teachingprovided herein, numerous other applications of the phototherapy devicesand/or systems described herein will be available to one of skill in theart.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A device, said device comprising: a first lightsource that produces a light that comprises or consists of a bluespectral component and/or green spectral component wherein lightcomprising said blue and/or green spectral component is a blinkinglight; and a second light source comprising a blinking light source thatproduces a light lacking a blue and/or green spectral component or wherethe blue and/or green spectral component produced by said second lightsource is smaller than the blue and/or green spectral component of thelight produced by said first light source; wherein said first lightsource and said second light source are configured to emit light insubstantially the same direction to provide illumination that is thecombination of illumination from said first light source and said secondlight source wherein: i) the color temperature difference (ΔT) betweenthe first light source and the second light source is about 50K or less;ii) for each light source the distance to a black-body locus (D_(uv)) isless than about 0.01, iii) the difference in intensity between the firstlight source and the second light source is less than about 100 lux; andiv) the difference in illumination angle between the first light sourceand the second light source is less than about 30 degrees; so thatlooking directly into the two lamps with the human eye, the two lightsources will appear substantially identical in color and intensity; anda controller that is configured to control a blink frequency of saidfirst light source and the a blink frequency of said second lightsource, a phase delay between blinking of said first light source, and aduty cycle of said first light source and said second light source, andwherein: said controller is configured to provide continuous blinking ofsaid first light source and said second light source when said device isturned on; and said controller is configured to control the blinking ofsaid first light source and said second light source so that theblinking of said first light source and the blinking of said secondlight source are 180 degrees out of phase with each other to produce acombined illumination that has a substantially constant illuminationintensity and color.
 2. The device of claim 1, wherein: said first lightsource produces a light that comprises or consists of a blue spectralcomponent; and said second light source that produces a light lacking ablue spectral component or where the blue spectral component produced bysaid second light source is smaller than the blue spectral component ofthe light produced by said first light source.
 3. The device of claim 2,wherein a blue light comprising said first light source, or the bluespectral component of said first light source, is in the wavelengthrange from about 440 nm up to about 495 nm.
 4. The device of claim 3,wherein the blue light comprising said first light source, or the bluespectral component of said first light source has a maximum emission atabout 460 nm.
 5. The device of claim 2, wherein said first light sourceprovides an irradiance that is larger than 5 mW/nm/m² in a wavelengthrange from 440 nm up to 500 nm.
 6. The device of claim 1, wherein: saidfirst light source blinks at a frequency that ranges from about 20 Hz upto about 50 Hz; and said second light source blinks at a frequency thatranges from about 20 Hz up to about 50 Hz.
 7. The device of claim 6,wherein said first light source blinks at a frequency of about 40 Hz andsaid second light source blinks at a frequency of about 40 Hz.
 8. Thedevice of claim 7, wherein said first light source provides a luminousintensity ranging from 10 lm up to 10,000 lm.
 9. The device of claim 6,wherein: said first light source produces blinks that have a durationthat ranges from about 5 ms up to about 20 ms; and said second lightsource produces blinks that have a duration that ranges from about 5 msup to about 20 ms.
 10. The device of claim 1, wherein the duty cycle ofsaid first light source and/or said second light source ranges from 5%up to 90%.
 11. The device of claim 10, wherein the duty cycle of saidfirst light source and/or said second light source is 50%.
 12. Thedevice of claim 1, wherein the ratio of duty cycle of said first lightsource to said second light source ranges from 1:2 to 2:1.
 13. Thedevice of claim 12, wherein the ratio of duty cycle of said first lightsource to the duty cycle of said second light source is about 1:1. 14.The device of claim 1, wherein: said first light source has a colortemperature that ranges from about 2700K up to about 3500K; and saidsecond light source has a color temperature that ranges from about 2700Kup to about 3500K.
 15. The device of claim 14, wherein the difference incolor temperature between said first light source and said second lightsource is less than 30K.
 16. The device of claim 14, wherein thedifference in color temperature between said first light source and saidsecond light source ranges from 5K up to 10K.
 17. The device of claim16, wherein the difference in color temperature between said first lightsource and said second light source ranges from 0.5K up to 5K.
 18. Thedevice of claim 1, wherein said first light source provides a luminousintensity ranging from 10 lm up to 5,000 lm.
 19. The device of claim 1,wherein a distance to the black body locus D_(UV) for said first lightsource and said second light source is 0.0001 or less.
 20. The device ofclaim 1, wherein the difference in illumination intensity between saidfirst light source and said second light source is less than 100 lux.21. The device of claim 20, wherein the difference in intensity betweensaid first light source and said second light source is less than 5 lux.22. The device of claim 21, wherein the difference in intensity betweensaid first light source and said second light source is less than 2 lux.23. The device of claim 1, wherein said first light source and/or saidsecond light source comprises one or more light emitting diodes (LEDs).24. The device of claim 23, wherein the first light source and/or thesecond light source comprises at least one different LED for eachspectral component.
 25. The device of claim 1, wherein: said first lightsource and said second light source are disposed in a diffuser; and/orsaid device comprises a luminaire; or said device comprises a table lampor an overhead lamp; or said device is configured for mountingproximate, at, and/or attached to a frame of a window; or said devicecomprises a face or eye mask in that directs illumination from both saidfirst light source and said second light source to each eye.
 26. Amethod of treating a subject having a neurodegenerative conditionselected from the group consisting of dementia, mild cognitiveimpairment, and Alzheimer's disease, said method comprising: using adevice of claim 1 to expose said subject to blinking blue light in thewavelength range from 440 nm up to 495 nm at a frequency ranging from 20Hz up to 60 Hz, at an intensity and duration sufficient to mitigate asymptom, or slow or stop the progression of said neurodegenerativecondition; and where the illumination produced by said second lightsource supplements the illumination produced by the first light sourceso that the blinking of said first light source when combined with thelight from said second light source is substantially undetectable bysaid subject.
 27. The method of claim 26, wherein the blue light or bluespectral component of a light has a maximum at about 460 nm.
 28. Themethod of claim 26, wherein: said method comprises ameliorating one ormore symptoms of Alzheimer's disease, and/or reversing Alzheimer'sdisease, and/or reducing the rate of progression of Alzheimer's disease;and/or said method comprises preventing or delaying the onset of apre-Alzheimer's condition and/or cognitive dysfunction, and/orameliorating one or more symptoms of a pre-Alzheimer's condition and/orcognitive dysfunction, or preventing or delaying the progression of apre-Alzheimer's condition or cognitive dysfunction to Alzheimer'sdisease; and/orsaid method is a method of preventing or delaying thetransition from a cognitively asymptomatic pre-Alzheimer's condition toa pre-Alzheimer's cognitive dysfunction; and/or said method is a methodof preventing or delaying the onset of a pre-Alzheimer's cognitivedysfunction, or ameliorating one or more symptoms of a pre-Alzheimer'scognitive dysfunction; and/or said method comprises preventing ordelaying the progression of a pre-Alzheimer's cognitive dysfunction toAlzheimer's disease; and/or said method produces a reduction in the CSFof levels of one or more components selected from the group consistingof Aβ42, sAPPβ, total-Tau (tTau), phospho-Tau (pTau), APPneo, solubleAβ40, pTau/Aβ42 ratio and tTau/Aβ42 ratio, and/or an increase in the CSFof levels of one or more components selected from the group consistingof Aβ42/Aβ40 ratio, Aβ42/Aβ38 ratio, sAPPα, sAPPα/sAPPβ ratio,sAPPα/Aβ40 ratio, and sAPPα/Aβ42 ratio; and/or said method produces areduction of the plaque load in the brain of the subject; and/or saidmethod produces a reduction in the rate of plaque formation in the brainof the subject; and/or said method produces an improvement in thecognitive abilities of the subject; and/or said method produces animprovement in, a stabilization of, or a reduction in the rate ofdecline of the clinical dementia rating (CDR) of the subject.
 29. Amethod of treating depression, short-term memory loss, of improvingmemory, of improving cognition, of improving sleep, and/or of improvingathletic performance in a subject, and/or synchronizing a circadianrhythm to local time, said method comprising: using a device of claim 1to expose said subject to blinking blue light in the wavelength rangefrom about 440 nm up to about 495 nm at a frequency ranging from about20 Hz up to about 60 Hz, at an intensity and duration sufficient tomitigate a symptom of depression, or to mitigate short-term memory loss,or to improve memory, or to improve cognition, or to improve sleep,and/or to improve athletic performance in said subject; and where theillumination produced by said second light source supplements theillumination produced by the first light source so that the blinking ofsaid first light source when combined with the light from said secondlight source is substantially undetectable by said subject.